doi: 10.1161/CIRCULATIONAHA.105.598698
(Circulation. 2006;114:2178-2189.)
© 2006 American Heart Association, Inc.
Basic Science for Clinicians |
Heme Oxygenase-1
A Novel Drug Target for Atherosclerotic Diseases?
From the Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney, Australia (R.S.), and Pulmonary and Critical Care Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (M.A.P.).
Correspondence to Roland Stocker, Centre for Vascular Research, School of Medical Sciences, Faculty of Medicine, University of New South Wales, UNSW Sydney, Australia. E-mail r.stocker{at}unsw.edu.au
Key Words: atherosclerosis • cardiovascular diseases • endothelium • inflammation • metabolism • pharmacology • vasodilation
 |
Introduction |
|---|
 Top Introduction HO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
Schmid and coworkers1 were the first to report on the presence of heme oxygenase (HO) in liver microsomes capable of degrading heme to bilirubin, and this activity was subsequently dissociated from cytochrome P-450.2,3 HO catalyzes the first and rate-limiting step in the oxidative degradation of heme (Fe-protoporphyrin-IX) to carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin-IX (Figure 1). The enzyme binds heme in a 1:1 molar complex, and HO-bound heme acts as prosthetic group and substrate. The reaction requires 3 molecules of molecular oxygen (O2) per heme molecule oxidized and reducing equivalents derived from nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide (reduced form) and transferred to the oxygenase via nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase. Regiospecific oxidation of heme is achieved in a stepwise reaction, with
-meso-hydroxyheme and verdoheme as intermediates, and the dissociation of CO followed by that of Fe2+.4 The release of biliverdin from HO is accelerated by biliverdin reductase, which reduces the green pigment to bilirubin-IX,4 which is then excreted into bile as the glucuronic acid conjugate.
|
Originally, the interest in HO was related to its well-established function in heme catabolism and the turnover of erythrocytes. For many years, CO and bilirubin were regarded as toxic waste byproducts of the HO reaction, but in 1987, a potential beneficial role of bilirubin was proposed5 based on the in vitro antioxidant activities of the pigment. Over the last decade, however, the interest in HO has shifted greatly from a metabolic to a protective function of the enzyme in a variety of conditions associated with cellular stress and pathologies, and this has been the subject of excellent recent reviews.6,7
The relationship of HO to atherosclerotic vascular disease was suggested initially in 1994 by an observational study reporting that low serum concentrations of bilirubin are associated with increased risk of coronary artery disease.8 Since then, the implied cardioprotective role of HO has been developed and substantiated significantly in experimental models of atherosclerotic vascular disease, including atherosclerosis,9 intimal hyperplasia,10 and myocardial infarction.11 There is now good evidence that induction of the inducible isozyme HO-1 by a broad spectrum of physical and chemical agents leads to several vascular cell-specific protective activities in the setting of inflammatory atherosclerotic diseases. Despite this recent work, however, the precise relationship between HO-1 and atherosclerosis remains unknown. In the present study, we review recent progress in our understanding of the protective mechanisms of HO-1 in atherosclerotic vascular disease and highlight areas of insufficient knowledge that require additional work in the future.
|
HO-1: Critical Contribution to Iron Homeostasis |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
A discussion of the role of HO-1 in atherosclerotic vascular disease should begin with a brief review of the established role of the enzyme in iron homeostasis. HO-1 in macrophages of the reticuloendothelial system plays a key role in the reuse of the iron essential for erythropoiesis. In adult humans, the majority of Fe-protoporphyrin-IX degraded by HO-1 is derived from hemoglobin, resulting in a daily production of
28 mg Fe2+ or nearly 1% of the total body iron store.12 This iron is returned almost quantitatively to the circulation where it is bound tightly by the plasma glycoprotein transferring, which transports the iron to the bone marrow where it is used to synthesize hemoglobin in developing erythroid cells. Indeed, mice lacking functional HO-1 develop an anemia that is associated with abnormally low levels of serum iron and the accumulation of iron in liver and kidneys.13 This function of HO-1 in iron homeostasis implies that at least in macrophages, HO-1 activity is associated with the release of cellular iron. In the context of atherosclerotic vascular diseases, it is not clear whether a role of HO-1 in iron reuse extends to macrophages, or indeed to other cells, in the vessel wall and/or to heme derived from sources other than hemoglobin. Ferris et al14 reported decreased iron efflux from fibroblasts deficient in HO-1 compared with control cells and transfection of an epithelial cell line with HO-1 to augment iron release without changes to the cellular iron storage protein ferritin. In apparent contrast, an earlier study reported Ultraviolet A radiation induced HO-1 activity to co-induce ferritin and that ferritin to store released iron.15 Homeostasis of cellular iron is accomplished by coordinated regulation of iron import and export proteins.16 Export of iron to transferrin is generally thought to occur via the plasma membrane transporter ferroportin, and this requires oxidation of Fe2+ to Fe3+ by ceruloplasmin.16 In vitro vascular endothelial cells express ferroportin in response to high glucose17 and proinflammatory cytokines.18 It is not known, however, whether this extends to endothelial and/or vascular smooth muscle cells in vivo, whether ferroportin expression is responsive to increased cellular HO-1 activity, or whether ceruloplasmin is present in atherosclerotic vessels. What is known is that arteries with atherosclerotic lesions express HO-119 and contain more iron than corresponding healthy vessels.20 Because iron can conceivably affect atherosclerotic disease, investigations of the role of HO-1 on iron content in diseased arteries are warranted. In addition, the possibility that non–bone marrow HO-1 supplies iron for growth of nonerythroid stem cells, such as endothelial progenitor cells implicated in the repair of vascular injury relevant to atherosclerotic vascular disease, deserves investigation.
|
HO-1: Functions Beyond Iron Homeostasis |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
There are 2 genetically distinct isozymes of HO: the inducible HO-1 and a constitutively expressed form, HO-2. As indicated, HO-1 is expressed most strongly in tissues involved in erythrocyte or hemoglobin metabolism, whereas in most other tissues, HO-1 typically occurs at low basal levels but responds rapidly by transcriptional activation to diverse stimuli. In contrast, HO-2 is strongly expressed in testes but also is present ubiquitously in other tissues, including the vasculature, and it does not generally respond to transcriptional activation. HO-1 is classically characterized as a protein associated with the endoplasmic reticulum,1 although recent evidence suggests that the enzyme also is present in caveolae of the plasma membrane of endothelial cells7 and in liver mitochondria of heme-treated rats.21 A function of nonmicrosomal HO-1 currently is not established, although the reported colocalization of biliverdin reductase21 suggests that the enzyme is also metabolically active at these sites and hence may contribute to a localized regulation of heme protein turnover.
|
HO-1: Protection Against Atherosclerotic Disease |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
HO-1 is a cytoprotective enzyme, and its induction commonly occurs in the setting of increased cellular stress to help maintain physiological homeostasis. HO-1 is induced by a number of stressors,7 and one may predict that risk factors for the development of coronary heart disease and other cardiovascular disease processes will mediate HO-1 expression. In fact, this is the case because increased blood pressure22 and altered laminar flow in blood vessels,23 advanced glycation end products,24 cigarette smoke,25 oxidized lipids,26 and a multitude of systemic inflammatory processes7 lead to increased cellular HO-1 expression. Moreover, this constellation of processes that lead to HO-1 induction may suggest a role for HO-1 in mediating the cardiovascular disease processes associated with obesity and metabolic syndrome,27 which have become significant public health problems. Pragmatically determining that upregulation of HO-1 plays a protective role in atherosclerotic disease would require investigation into patients who either lack HO-1 or do not robustly express HO-1 in the presence of risk factors for coronary heart disease. With the availability of these patients, investigations into the prevalence of coronary heart disease would provide critical insight into the physiological role of HO-1.
HO-1 deficiency is very rare in humans; however, an autopsy report from a 6-year-old boy with HO-1 deficiency revealed hyperlipidemia associated with fatty streaks and fibrous plaques in the aorta.28 The concept that HO-1 may be causally related to cardiovascular diseases in humans also has been suggested by studies assessing polymorphisms in the 5'-flanking sequence of the human HO-1 gene.29 Different polymorphisms have been identified in the HO-1 promoter, with the most studied being (GT)n dinucleotide-length polymorphism. In general, the belief is that compared with longer (GT)n repeats, shorter (GT)n repeats have higher transcriptional activity and thus higher expression levels. For example, in a Chinese population of type II diabetic patients, long (GT)n repeats (
32 GTs) were associated with increased risk for coronary artery disease.30 Conversely, in a Japanese population of patients with significant risk factors (hyperlipidemia, diabetes, and smoking) for coronary artery disease, shorter (GT)n repeats (<27 GTs) were associated with less disease.31 However, this concept does not appear to hold for white patients with myocardial infarctions or stable coronary artery disease.32 In contrast, studies assessing the association of length of (GT)n repeats with the risk of restenosis after percutaneous transluminal angioplasty have been more consistent across ethnic backgrounds.29,33 In addition to (GT)n dinucleotide-length polymorphism, a single nucleotide polymorphism in the HO-1 promoter, T(-413)A, correlated with a reduced incidence of ischemic heart disease in a Japanese population.34 In this study, the AA genotype (A on each allele) at position –413 was less likely to be associated with myocardial infarction and angina pectoris, and cell culture experiments suggested the AA genotype to have significantly higher basal promoter activity that was independent of the length of (GT)n repeats.34 These studies advocate the potential role of HO-1 gene regulation in atherosclerotic disease processes. Truly understanding HO-1 as a modulator of atherosclerosis, however, requires further in-depth investigation into this specific disease process.
Atherosclerosis is an inflammatory disease in which lipid deposition in the arterial wall, resulting from elevated levels of plasma cholesterol, is central to lesion development. This process involves the uptake of modified low-density lipoprotein (LDL) by macrophages and is associated with a state of heightened oxidative stress and damage.35 As atherosclerotic lesions progress, migration and proliferation of smooth muscle cells and deposition of fibrous tissue lead to an advanced, complicated lesion. Wang and colleagues19 previously demonstrated that expression of HO-1 is prominent in endothelial cells, macrophages, and foam cells in human and animal atherosclerotic lesions. Ishikawa and colleagues36,37 showed that inducers of HO-1 reduce lesion size in Watanabe heritable hyperlipidemic rabbits36 and LDL-receptor–deficient mice.37 Using adenovirus-mediated gene transfer of HO-1, Juan and colleagues38 demonstrated that selective overexpression of HO-1 decreases lesion size in apolipoprotein E–deficient (ApoE–/–) mice.
There are additional lines of evidence in support of HO-1 playing a protective role in atherosclerotic lesion formation (the Table). Long-term inhibition of the HO activity using metalloporphyrins promotes lesion formation in LDL-receptor–deficient mice37 and rabbits.36 A potentially serious limitation of these studies, however, is that metalloporphyrins are not selective for HO-1 or even the HO system,39 particularly when used at high doses. Thus, the use of HO-1–deficient (HO-1–/–) mice was important to specifically establish a protective role of endogenous HO-1 in atherosclerosis. For this, Yet et al9 subjected ApoE–/– mice and mice deficient in ApoE and HO-1 (ApoE–/–HO-1–/–) to a Western diet for 8 weeks and then analyzed them for the development of atherosclerosis. Despite similarly elevated total plasma cholesterol, ApoE–/–HO-1–/– mice had larger and more advanced lesions than ApoE–/– mice. The lesions in ApoE–/–HO-1–/– mice were complicated with fibrous caps, comparable to plaques seen in ApoE–/– mice on a Western diet for longer periods of time (12 weeks). These results, in conjunction with the HO-1 gene transfer studies, provide strong evidence for a beneficial effect of HO-1 on experimental atherosclerosis.
|
When evaluating the potential for HO-1 as a therapeutic target, we should also assess the ability of HO-1 to ameliorate vascular complications after coronary artery bypass surgery or percutaneous transluminal angioplasty, namely vein graft failure and restenosis. Although coronary artery stenting is being used increasingly to treat patients with obstructive atherosclerotic lesions, coronary artery bypass graft surgery remains an important treatment for multivessel disease. Autologous vein grafts provide a convenient conduit for bypass graft surgery, and although early grafts occlude as a result of thrombotic events, late-onset graft occlusion is the result of intimal thickening and superimposed atherosclerosis. In experimental vein graft stenosis, HO-1–/– mice develop more robust neointima consisting of smooth muscle cells 10 days after surgery than wild-type mice,9 suggesting that HO-1 plays a protective role in the pathophysiology of not only atherosclerosis but also vein graft failure.
As indicated, studies assessing human HO-1 polymorphisms in disease suggest that higher levels of HO-1 expression are associated with a reduced risk for restenosis after percutaneous transluminal angioplasty.29 This concept has been confirmed in animal models of restenosis. Thus, adenovirus-mediated transfer of the HO-1 gene reduces intimal thickening in balloon-injured pig femoral10 and rat carotid arteries.40 Conversely, arterial lesions induced by wire injury are more severe in HO-1–/– than wild-type mice,10 again establishing a protective role for HO-1 in models of injury-induced vascular disease. Together, the above results strongly support the notion that HO-1 plays a protective role in experimental atherosclerotic vascular disease. Although the relevance of these findings to the human disease has yet to be established, the overall outcome of the preclinical studies carried out to date clearly points to HO-1 as a potential novel target for therapy.
|
Induction of HO-1 |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
Signaling Pathways
The gene coding for HO-1 is highly regulated, and in most cell types, HO-1 is expressed in response to numerous stimuli.7 Interestingly, the overwhelming majority of stimuli cause a rapid and temporary induction of the HO-1 gene; only a few mediators that suppress HO-1 are known.41 Regulation of the HO-1 gene is predominantly at the transcriptional level.7 Multiple enhancer regions have been identified in the 5'-flanking sequence of the HO-1 gene, and depending on the specific stimulus and the cell type involved, various transcription factors will interact with their cognate DNA binding domains in the HO-1 promoter to regulate gene transcription. One of the first pathways to link extracellular stimuli to activation of HO-1 is the mitogen-activated protein kinase (MAPK) pathway.7 The MAPKs are a family of serine-threonine protein kinases that regulate many cellular events, including responses to environmental stimuli. The MAPK pathway encompasses 3 signaling cascades (ie, extracellular signal regulated kinases 1/2, c-Jun-N-terminal kinase, and p38-MAPK) that phosphorylate downstream targets. In the case of HO-1 transcriptional events, downstream targets of these kinase cascades are transcription factors involved in HO-1 gene regulation. Beyond the MAPKs, other kinases that have emerged as mediators of HO-1 gene regulation include phosphatidylinositol 3-kinase and protein kinases A, C, and G.7
We have already mentioned that genetic polymorphisms in the human HO-1 gene promoter modulate the level of transcriptional activity and the magnitude by which HO-1 responds to a pathophysiological stimulus. These polymorphisms are associated with an altered risk profile for cardiovascular disease.29 To date, little is known about the interaction of nuclear proteins within these polymorphic regions. However, a number of excellent reviews have covered the complex topic of HO-1 gene regulation by transcriptional events involving classic DNA binding domains and their associated transcription factors, as well as cell type and species specificity (see Reference 7 and references therein). Therefore, for the purposes of the present review, we focus on selected transcriptional events activated by proatherogenic stimuli.
There are several critical regulatory domains present in a 10-kb region of the 5'-flanking sequence of the HO-1 gene. Two of the most highly studied enhancer regions, called E1 and E2, contain stress-response elements (StRE) that are conserved between human, mouse, and rat genes and that structurally resemble the antioxidant response element (ARE) and the AP-1/TPA, Maf, and cyclic adenosine monophosphate (cAMP) response elements.7 Nuclear proteins that bind to these elements belong to the basic-leucine zipper (bZIP) superfamily of transcription factors and include AP-1 (Fos/Jun), CREB/ATF, Maf, Cap’n’collar-bZIP (Nrf, Bach), and biliverdin reductase.42 These nuclear proteins bind to StRE as homodimers or heterodimers (within or between families). Because of the similarity of StRE with consensus AP-1 binding sites, complexes such as c-Fos/c-Jun heterodimers were the focus of initial HO-1 gene regulation studies.43 However, more recent studies have emphasized additional bZIP family members as important mediators of the StRE response. For example, during exposure to heme or heavy metals, cytosolic Nrf2 is stabilized and then translocates to the nucleus, where it binds to consensus StRE/ARE binding sites and forms heterodimers with Maf proteins. Because Maf proteins do not have transactivation domains, Nrf2 drives transcriptional activity. The heme binding protein Bach1 is another binding partner for Maf proteins at StRE/ARE sites. Because Bach1 also lacks a transactivation domain, its heterodimerization with Maf proteins results in repression of HO-1 expression. Heme, the substrate for HO-1 enzyme activity, abrogates the repression of Bach1 by inhibiting its binding to DNA.44 This inhibition of Bach1 binding allows activators of the HO-1 gene such as Nrf2 to bind with Maf proteins at StRE/ARE sites45 and thus provides a feedback loop for the regulation of HO-1 expression. The potential importance of Bach1 in cardiovascular disease is supported by the recent finding that mice deficient in Bach1 have increased expression of HO-1 and less intimal proliferation after vascular (cuff) injury.46
In addition, enhancer regions outside E1 and E2 also have been described in the transcriptional regulation of HO-1.7 For example, a balance of Ets protein family members, including transcriptional activators such as Ets-1 and Ets-2, and the repressor Elk-3 regulates the overall transcriptional response of HO-1 during an inflammatory stimulus by binding to domains far downstream from the E1 and E2 enhancer regions.47 This demonstrates the complexity of the system and underscores the importance of differences in HO-1 gene regulation by different stimuli and in different cell types.
Response to Physical Stress
Increased synthesis of HO-1 protein in response to physical and chemical stress occurs commonly and in most tissues examined.7 This is not surprising when we consider that HO-1 belongs to a larger family of stress proteins in which transcriptional regulation responds to altered environmental conditions. In fact, HO-1 was initially referred to as 32-kDa heat shock protein because of its transcriptional responsiveness to hyperthermia,48 although the protein shares little amino acid homology with heat shock proteins, nor does it display protein chaperone activity. More recently, it has been reported that in cultured vascular smooth muscle cells, endoplasmic reticulum stress increased HO-1 mRNA and protein via the ARE, and this was associated with cell survival.49 The "endoplasmic reticulum stress response" constitutes a general response to endoplasmic reticulum–associated stress such as unfolded proteins, glucose starvation, and disruption of intracellular calcium homeostasis. Endoplasmic reticulum–initiated cell death pathways are increasingly recognized as playing important roles in several diseases, including ischemia/reperfusion injury, heart disease, and diabetes.
In addition to these general types of physical stress, HO-1 responds directly to vascular injury such as that which occurs during angioplasty.10 This response appears to be biphasic, with an initial decrease in endogenous HO-1 followed by an increase to above baseline and then a return to background levels of HO-1 expression.10,50 Furthermore, the temporal and spatial pattern of HO-1 expression appears to be similar to that of the G1 cyclin-dependent kinase inhibitors p27Kip1 and p21Cip,10, consistent with the notion that HO-1 functions upstream of and participates in the regulation of smooth muscle cell proliferation in injured vessels.
Response to Chemical Stress
As reviewed previously,7 HO-1 regulation responds to a large and broad spectrum of chemical stresses, including agents that cause oxidative stress or diminish oxygen, thiol-reactive agents, heavy metals, electrophilic polyphenolic compounds, inflammatory mediators, growth factors, hormones, and environmental pollutants. The following discussion is limited to agents directly relevant to atherosclerotic vascular disease.
As we have learned already, atherosclerotic vascular disease is characterized by a state of heightened oxidative stress that includes the presence of oxidized lipids,35 and HO-1 is expressed in atherosclerotic lesions.19 In vitro studies have demonstrated that hydrogen peroxide,51 linoleic acid hydroperoxides,52 oxidized phospholipids53 and LDL54 induce HO-1 in different cell types. When investigated, this induction was shown to be mediated via StRE/ARE in murine and human cells.53 However, whether increased levels of hydrogen peroxide and/or oxidized lipids directly induce HO-1 in atherosclerotic lesions is unclear at present. Hepatic HO activity is unaltered in mice deficient in glutathione peroxidase-1 or selenoprotein P (ie, enzymes involved in the cellular metabolism of hydrogen peroxide and lipid hydroperoxides) but increased in mice deficient in thioredoxin reductase,55 an enzyme that affects several redox-related cellular processes.35
Response to Therapeutic Agents
An increasing number of therapeutic agents have been reported to induce HO-1, in direct support of the notion that HO-1 may represent a novel drug target for atherosclerotic disease. These therapeutic agents include statins, rapamycin, paclitaxel, nitric oxide (NO), aspirin, and probucol. At micromolar concentrations, several statins dose dependently induce HO-1 in the human epithelial cell line ECV30456 and vascular smooth muscle cells.57 In addition, oral administration of statins at 100 mg/kg body weight resulted in a statin- and tissue-specific increase in HO-1 mRNA and protein in mice.58 Because this induction was associated with beneficial cellular effects such as increased resistance to oxidative stress and inhibition of smooth muscle cell proliferation,57 it was speculated that this novel activity may contribute to the pleiotropic and antiatherogenic actions of statins. While attractive, additional studies are required to establish whether statins at concentrations pharmacologically relevant to humans induce HO-1 and, if so, whether this indeed results in significant protection.
Rapamycin (sirolimus) is a macrolide antibiotic with potent immunosuppressive properties that inhibits cell proliferation by blocking the progression of cells from the G1 to the S phase of the cell cycle. In experimental models, rapamycin has antiproliferative properties against vascular endothelial and smooth muscle cells,59 and it reduces the fibroproliferative response to vascular injury in vivo.60 This has led to its successful clinical application in the form of sirolimus-eluting stents for the treatment of in-stent restenosis. Rapamycin induces HO-1 expression in primary human endothelial and smooth muscle cells,61 an activity not shared by other immunosuppressive agents such as cyclosporin A. In addition, inhibition of HO activity by tin protoporphyrin resulted in a loss of the antiproliferative activity of rapamycin,61 and smooth muscle cells from HO-1–/– mice were refractory to growth inhibition by rapamycin.62 Similarly, rapamycin was recently reported to induce HO-1 in the lungs of rats and to inhibit the development of monocrotaline-induced pulmonary hypertension, with the protective effect being blocked by co-treatment of the animals with tin protoporphyrin.62 Collectively, these findings suggest that the antiproliferative action of rapamycin may be modulated, at least in part, by its actions on HO-1. Similar to rapamycin, paclitaxel, which induces apoptosis, interferes with normal function of microtubule growth, and is used to treat in-stent restenosis, induces HO-1 in vascular smooth muscle cells.63
Nitroglycerin and long-acting nitrates are used commonly in cardiovascular medicine for various anginal syndromes and congestive heart failure and in patients with left ventricular dysfunction. The mechanisms for relief of myocardial ischemia by nitrates are intimately linked to the formation of NO within vascular smooth muscle cells, where it stimulates the enzyme guanylate cyclase, resulting in increases in guanosine 3',5'-cyclic monophosphate (cGMP) and vasodilation. In addition to regulating vascular tone, it is now increasingly recognized that NO modulates a variety of important physiological activities related to vascular homeostasis, including platelet aggregation, leukocyte trafficking, cell signaling, and the migration and growth of endothelial and smooth muscle cells. NO donors64 and pure, gaseous NO65 induce HO-1. This induction is due, in part, to the increased stability of HO-1 mRNA65 and extends to many different forms of NO (eg, NONOates, S-nitrosothiols, sodium nitroprusside, and pentaerythritol tetranitrate) and vascular cells.7 Activation of soluble guanylate cyclase and enhanced formation of cGMP have commonly been associated with HO-1 induction by NO and related compounds.7 However, this is not the case in all situations, just as not all NO-related compounds induce HO-1. Perhaps most notably, induction of HO-1 in human embryonic lung fibroblasts by gaseous NO was reported to be independent of the guanylate cyclase/cGMP pathway,65 and isosorbide dinitrate, unlike pentaerythritol tetranitrate, was unable to induce HO-1 in endothelial cells.66 The cellular generation of NO also may be responsible for, or contribute to, the ability of therapeutically used drugs such as aspirin67 to induce HO-1.
Probucol, a rarely used cholesterol-lowering drug, has been reported to inhibit atherosclerosis in carotid artery68 and neointimal proliferation after coronary angioplasty with69 and without70 stent deployment in humans and to retard atherosclerosis71 and intimal thickening after balloon injury in animals.72 Probucol has been reported to upregulate HO-1 mRNA, protein, and activity in smooth muscle cells in vitro after exogenous addition and in vivo after oral administration to animals undergoing vascular injury induced by balloon angioplasty.50 Blockade of HO-1 upregulation by siRNA and HO activity by tin protoporphyrin inhibited proliferation of vascular smooth muscle cells in vitro50 and in vivo, respectively.73 Interestingly, blocking the ability of probucol to induce HO-1 in vivo completely prevented the ability of the drug to inhibit intimal hyperplasia, promote reendothelialization,73,74 and restore endothelium-dependent relaxation of the injured blood vessel.73 Together, these findings indicate that induction of HO-1 is the mode of action of probucol and results in several concerted protective activities against atherosclerotic disease. Furthermore, as a result of in vivo structure-function studies, Wu et al73 proposed novel probucol analogs as potential new antiatherosclerotic therapeutics that act via HO-1 induction. Probucol has largely been withdrawn as a therapeutic drug because it failed to inhibit femoral atherosclerosis75 and because it has QT-prolonging and high-density lipoprotein cholesterol–lowering activities.69 However, the monosuccinate ester of probucol (AGI-1067) is presently being tested in phase 3 clinical trials as an antiatherosclerotic agent. Like probucol, AGI-1067 inhibits neointimal proliferation after coronary stenting in humans.69 Unlike probucol, however, AGI-1067 does not appear to prolong the QT interval, and it has comparatively less high-density lipoprotein cholesterol–lowering activity.69 Interestingly, we observed recently that AGI-1067 also induced HO-1 in injured arteries of experimental animals (B.J. Wu and R. Stocker, unpublished observation, 2006).
Collectively, the above results are consistent with the notion that targeting HO-1 is a promising and therapeutically feasible approach against atherosclerotic66,73,76,77 and cardiovascular-renal disease.6 A potential problem with this approach, however, is that the chemical upregulation of HO-1 commonly involves Nrf2/ARE, as we learned earlier. The importance of this is that the Nrf2/ARE signaling pathway also causes induction of a phase II response,78 an undesirable effect in relation to the development of novel drugs. Given the complexities involved in HO-1 regulation, an alternative therapeutic may be the application of a single metabolic product of HO activity such as the CO-releasing molecules79 or biliverdin and bilirubin. Preclinical trials suggest that this is a promising approach,80–82 although there are concerns about using the bile pigments in intervention studies such as their poor chemical characterization and water solubility83 and their potential toxicity.
|
Prolonged and High Levels of HO-1 Expression |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
After reviewing the regulation of HO-1, from the basic level of gene transcription to the in vivo level during disease, we must raise the question of whether prolonged induction or high levels of HO-1 expression have adverse consequences. As HO-1 degrades heme, long-term increases in HO-1 or induction of HO-1 to high levels of expression could conceivably lead to heme depletion and associated adverse consequences such as loss of cellular heme proteins required for normal cell function. Contrary to such an expectation, however, the prolonged induction of high levels of HO-1 seen in genetically mutant mice with hemolytic anemia does not lead to changes to microsomal heme content or heme biosynthesis.84 In fact, it has been proposed that in vivo the extent of heme degradation and heme synthesis is carefully balanced by corresponding long-term adaptive responses.84 Several independent studies have demonstrated a beneficial effect of targeted overexpression of HO-1 in experimental models of cardiovascular disease. Cardiac-specific overexpression of HO-1 in mice and rats provides improved recovery of contractile performance and long-term myocardial protection after ischemia/reperfusion in an HO-1 dose-dependent manner, with the greatest protection at the highest level of HO-1 expression.11,85 In addition, in a mouse model of chronic hypoxia, sustained increases in the human HO-1 transgene targeted to the lung ameliorated pulmonary vascular hypertension, vessel wall hypertrophy, and inflammation.86 Furthermore, targeting HO-1 to vascular smooth muscle cells, resulting in long-term increases in HO-1 expression, decreased angiotensin II–induced production of reactive oxygen species and inflammatory responses in transgenic mice.87 Despite this, however, further studies are needed to unambiguously rule out the possibility of adverse effects of prolonged HO-1 expression because the biological effects of HO-1 are different in different cell types and in different pathological settings. In this context, it is also important to point out that there may be differences between situations of long-term versus short-term HO-1 induction, eg, with regard to the impact on heme content and activities of heme-containing enzymes. Thus, short-term induction of HO-1 expression and HO activity in rats by treatment with hemin is associated with decreased mitochondrial heme content and activities of cytochrome oxidase and NO synthase.21 Similarly, in vitro overexpression of HO-1 in endothelial cells can result in decreased cyclooxygenase activity.88
|
Proposed Mode of Protection |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
To date, studies investigating the mode of protection offered by HO-1 induction have been limited mostly to research examining the effects of the products derived from HO activity. For example, the ability of CO and biliverdin/bilirubin to prevent neointimal development after vascular injury has been examined in several independent studies. CO was reported to prevent balloon angioplasty–induced arteriosclerotic lesion formation in rats.89 Interestingly, this study showed that 1 hour of exposure to inhaled CO (250 ppm) before injury ameliorated lesion formation 14 days later.89 In addition, Öllinger and colleagues82 demonstrated neointimal formation after balloon injury to be reduced in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor to bilirubin, compared with control animals. This section discusses our present knowledge of how HO-1 and the products of its catalytic activity are thought to protect against atherosclerotic vascular pathology.
Inflammation
There is overall support for the concept that HO-1 is important in regulating inflammation in vivo. Compared with wild-type mice, HO-1–/– mice develop chronic inflammation with increasing age, characterized by enlarged spleens (due in part to follicular hyperplasia) and lymph nodes, hepatic inflammatory infiltrates, and high peripheral white blood cell counts.13 Notably, HO-1–/– mice also show hallmarks of vascular injury, indicated by monocytes adhering to vessel walls.13 Interestingly, death of the only person diagnosed to date with HO-1 deficiency was reported to be due to an inflammatory syndrome associated with vulnerability of endothelial cells to oxidative stress–induced injury.28 These reports suggest that HO-1 contributes to physiological homeostasis and that in the absence of HO-1, the potential for a proinflammatory environment develops.
It has been suggested that CO contributes significantly to the antiinflammatory properties of HO-1.76,90 For example, overexpression of HO-1 or the administration of CO suppresses proinflammatory cytokines and chemokines such as tumor necrosis factor-, interleukin-1ß, interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1ß,76,85,86,90 and increases the expression of the antiinflammatory mediator interleukin-10.91 This antiinflammatory effect of CO occurs in part via induction of peroxisome proliferator–activated receptor-
and blocking expression of Egr-1.92 Other beneficial properties of HO-1 and CO that may mediate the inflammatory response and blood flow during vascular injury include their ability to prevent platelet activation93 and subsequent thrombosis,94 to suppress plasminogen activator inhibitor type-1 expression,95 and to prevent endothelial cell death.96 In vitro, overexpression of HO-1 has been reported to decrease the expression of the adhesion molecules E-selectin and vascular cell adhesion molecule-1.97
Smooth Muscle Cell Proliferation
In addition to altering the inflammatory response, HO-1 and products of its enzymatic activity can prevent neointimal formation by inhibiting the proliferation of smooth muscle cells. Morita and colleagues98,99 originally provided some insight into the regulation of smooth muscle cell proliferation by HO-1 and CO using hypoxic conditions in vitro. These studies demonstrated that smooth muscle cell–derived CO was an important mediator of cell proliferation and that inhibiting CO formation or scavenging CO increased the growth of smooth muscle cells in response to endothelial mitogens such as endothelin-1 and platelet-derived growth factor-ß.98,99 It was also noted that CO had effects independent of the endothelium, increasing cGMP and suppressing E2F-1 (a transcription factor involved in cell cycle progression) in vascular smooth muscle cells.99 Advancing this biological activity into a model of vascular injury, Duckers and colleagues10 showed that HO-1 directly stimulated vascular relaxation and inhibited vascular cell proliferation in a model of vascular injury in pigs using adenoviral HO-1 gene transfer. Vessel relaxation was mediated via NO-independent activation of soluble guanylate cyclase and resulting increases in cGMP, whereas growth inhibition and cell cycle arrest were associated with induction of the cell cycle inhibitor p21Cip1.10 Further studies using a wire injury model in the femoral arteries showed that lesions in HO-1–/– mice were more severe than lesions in wild-type mice.10 Vascular smooth muscle cell proliferation was greater in lesions from HO-1–/– mice compared with HO-1+/+ mice, confirming the antiproliferative effect of HO-1 on arteries in vivo. In addition to activation of guanylate cyclase, CO may affect vascular tone by stimulating calcium-activated potassium channels in smooth muscle cells.100 More recent studies have shown that beyond CO, biliverdin decreased neointimal formation after balloon injury in rats compared with control animals.82 In this model, decreased smooth muscle cell proliferation was reported to be due, in part, to impaired activation of the p38-MAPK signaling pathway, resulting in the inhibition of cyclins D1, A, E, and cdk2 and thus a reduction in retinoblastoma protein phosphorylation.82 The culmination of these events is the arrest of cell cycle progression at the G1 phase and consequently inhibition of vascular smooth muscle cell growth.
Besides inhibiting smooth muscle cell proliferation, it has been suggested that HO-1 may contribute to cell death. This appears to occur in a cell-specific manner. HO-1–derived CO prevents apoptosis of endothelial cells,96 whereas in cultured vascular smooth muscle cells, transfer of the HO-1 gene or administration of biliverdin/bilirubin promotes apoptosis.101 The authors speculated that viral transfer of HO-1 gene might be a therapeutic means to treat occlusive vascular diseases. Given the importance of the growth of endothelial versus smooth muscle cells in the context of atherosclerotic vascular disease, these divergent responses of the 2 cell types to HO-1 and products of its catalytic activity emphasize the need to understand the cell-specific effects of HO-1 in disease. Probucol may serve as a useful example of this cell-specific action of HO-1. As mentioned, this drug inhibits smooth muscle cell proliferation while promoting endothelial cell growth and re-endothelialization in vivo,74 and both processes are completely blocked by Sn-protoporphyrin.73 In vitro, probucol induces HO-1 in smooth muscle but not endothelial cells.50
Vasodilation
Early suggestions of a dilatory action of HO-1 were attributed to an HO-mediated decrease in cytochrome P-450 content and activity,102 in part via binding of CO to cytochrome P-450. Subsequently, HO-1–mediated vessel relaxation was increasingly linked to CO-modulated physiological responses involving the NO-cGMP pathway.103 Indeed, overexpression of HO-1 in arteries was reported to stimulate vascular relaxation, mediated by guanylate cyclase and cGMP, independently of NO.10 More directly, experiments with CO-releasing molecules further validated a role for CO in vasodilation, although in this case, modulation of cGMP and ATP-dependent Ca2+ channels was thought to be involved.104 These studies provide strong support for the notion that high concentrations of CO can cause vasodilation. This is consistent with the overall increasing body of evidence confirming CO-mediated relaxation of different large and small vessels in different animals. CO likely acts via multiple mechanisms, including direct modulation of cGMP levels and K+ channels in smooth muscle cells and indirect effects via modulation of endothelium-dependent vasoconstrictors and via myogenic factors.7 It remains to be established however, how precisely this relates to HO-1 induction in vivo and to what extent CO is to be considered a signaling molecule in analogy to NO. With regard to vasodilation and other activities attributed to HO-1–derived CO, a missing piece of information is how much CO is actually produced in vivo in situations when HO-1 is induced. This is important because CO is 1000-fold less potent than NO as a relaxing agent.105 The situation is complicated further by the fact that depending on the situation, HO-2 also has the potential to significantly affect vessel relaxation.106 Furthermore, the ability of HO-1 and CO to dilate blood vessels is not a universal finding. In fact, emerging studies indicate that in some vascular beds, HO-1 and CO promote vasoconstriction by inhibiting the activity of endothelial NO synthase,107 which may lead to endothelial dysfunction and hypertension.108
Antioxidant Protection
Induction of HO-1 is commonly considered to enhance the antioxidant activity of cells and to provide in vivo protection against conditions associated with oxidative stress. Several lines of arguments support such a notion. For example, genetic evidence demonstrates that cells derived from HO-1–/– mice that lack functional HO-1 are less capable to withstand an oxidative challenge than the corresponding cells obtained from HO-1+/+ mice.9,109 Cultured HO-1–/– embryonic fibroblasts demonstrated elevated levels of reactive oxygen species when exposed to pro-oxidants such as hydrogen peroxide and paraquat, and they were hypersensitive to cytotoxicity caused by hemin and hydrogen peroxide.109 In addition, young adult HO-1–/– mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin,109 a condition associated with increased oxidative stress. Conversely, cells overexpressing HO-1 have been reported to be more resistant to oxidant-induced toxicity than the corresponding control cells.110
The underlying mechanism(s) for the increased antioxidant protection provided by HO-1 are less clear, although several lines of evidence point to an important role of a coordinated upregulation of the cytoprotective iron-binding protein ferritin.15,111 This may help to explain the surprising observation that after acute hyperoxic exposure, HO-1–/– mice had significantly decreased markers of lung oxidative injury than wild-type controls, which was reversed by transduction of human HO-1 in the knockout animals.112 There is also strong support for a role of HO-1–derived bile pigments in the enhanced antioxidant protection. Thus, it is now well established that biliverdin and bilirubin are efficient in vitro scavengers of different types of oxidants,113 and there is increasing evidence that this translates into cellular and possibly in vivo antioxidant activity. For example, when added at micromolar concentrations to cell culture media, bilirubin protects various cells, including endothelial and smooth muscle cells, against toxicity induced by hydrogen peroxide.114 In cells in which HO-1 is induced and exogenous hemin is provided as a substrate, increased resistance to oxidant-mediated toxicity is observed only while bilirubin formation takes place.114 Evidence for an in vivo antioxidant function of bilirubin is limited. Using Gunn rats as an experimental model of hyperbilirubinemia, however, Dennery et al115 showed that plasma of jaundiced rats exposed to hyperoxia showed decreased signs of oxidative damage than plasma from corresponding control animals.
It is not clear, however, how these apparently enhanced antioxidant activities provided by HO-1 upregulation result in increased protection against atherosclerotic disease. As discussed earlier for CO, a key unresolved question concerns the extent to which increased HO-1 activity augments the concentration of bile pigments in vivo. In this context, it is worth remembering that high concentrations of bilirubin are toxic. In addition, cultured cells are artificially depleted of several antioxidants (eg, vitamins C and E) that both protect cells from oxidant-induced damage and interact with bilirubin, so it is difficult to extrapolate results from in vitro cellular studies to the in vivo situation. In addition, although atherosclerosis is undoubtedly associated with a state of heightened oxidative stress, a causal link of this to disease and its outcome remains an unproven hypothesis, and there is a need to consider the possibility that oxidative damage within the diseased vessel wall is a bystander process of the disease.35 HO-1 has been identified repeatedly as a genetic factor in atherosclerosis that acts at the level of vessel wall endothelial cells. In these studies, the extent of induction of HO-1 by oxidized LDL has been reported to be associated with mice of a genetic background that predisposes to atherosclerosis,116 whereas one might have predicted the opposite outcome if HO-1 induction increased antioxidant activity and protected against atherosclerosis. An alternative interpretation is that endothelial cells from atherosclerosis-prone mice are more responsive to oxidized LDL, thus requiring HO-1 to be induced. In mice with a genetic background not predisposed to atherosclerosis, induction of HO-1 may not be needed.
|
Unifying Mechanisms |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
In the preceding sections, we have reviewed HO-1 induction and proposed resulting modes of protection against atherosclerotic disease (Figure 2). Given the multitude of different conditions and agents that have been reported to induce HO-1, as well as the various protective activities derived from HO-1 activity and its metabolic products, this section focuses on potential unifying principles involved in these processes. With regard to HO-1 induction, three general hypotheses have been proposed as unifying mechanism: a transient increase in cellular heme content, a transient increase in cellular reactive oxygen species levels, and an alteration in cellular thiol status.7 Although there is evidence in support of each of the 3 hypotheses, none of them singularly provide a satisfactory explanation. Thus, although the first hypothesis is important for HO-1 regulation induced by heme, the translocation of Nrf2, and the relief of transcriptional repression, many inducers such as thiol-reactive agents do not cause an initial increase in cellular heme. Similarly, the list of HO-1 inducers includes several phenolic antioxidants that are unlikely to cause cellular oxidative stress. On the other hand, there is a likely link between alterations in cellular thiol status and the level of reactive oxygen species, so thiol redox–mediated modification of the cytoplasmic factor Keap1 and related alterations in the nuclear translocation of Nrf2 could provide a general underlying mechanism for HO-1 regulation that involves redox processes.
|
A remarkable facet of the list of known HO-1 inducers is that these agents represent both stimulators and inhibitors of a particular disease process. For example, both proinflammatory (eg, tumor necrosis factor-117) and antiinflammatory cytokines (eg, interleukin-1091) have been reported to induce HO-1 in different cell types. Similarly, and more directly related to vascular disease, HO-1 inducers include pro-atherogenic stimuli (eg, hypoxia118) and agents with proven ability to attenuate vascular disease such as NO119 and probucol.50,73 The simplest interpretation of this apparent dichotomy is that induction of HO-1 represents both an endogenous protective response to and a therapeutic defense against atherosclerotic disease.
The knowledge we have gained over the last 5 to 10 years supports HO-1 as a protein that, when expressed, exhibits many activities that preserve vascular homeostasis. As such, HO-1 has clearly emerged as a therapeutic target that offers protection against atherosclerotic vascular disease (Figure 2). Indeed, Bach and colleagues76,77 have presented the view that HO-1 acts as a "therapeutic amplification funnel". In this model, the therapeutic effect of several molecules such as rapamycin, NO, and statins is mediated, in part, by one or more of the products of HO activity as a result of induction of HO-1.76,77 Amplification can be achieved in several ways, eg, by one of the HO-1-derived products inducing the formation of a molecule that upregulated HO-1 in the first place.76,77 Using HO-1 as a therapeutic means against atherosclerotic disease raises additional questions. How can regulating a single protein provide so many different modes of protection, and are all of these necessarily linked to the metabolic activity of the enzyme? Is a therapeutic approach aimed at modulating HO-1 activity superior to an approach based on the administration of a metabolic product? As experimental work continues, answers to these important questions will likely be found.120
|
Acknowledgments |
|---|
Sources of Funding
Dr Stocker acknowledges receiving financial support from the National Health & Medical Research Council of Australia (Senior Principal Research Fellowship 401106, program grant 222722, project grant 400992), the National Heart Foundation of Australia (project grant G 04S 1660), and infrastructure support from the New South Wales Capital Grants Scheme. Dr Perrella receives financial support from the NIH (grants HL60788, GM53249, and AI061246).
Disclosures
Dr Stocker received financial support from Merck Sharp & Dohme, Australia, and honoraria from Merck & Co, Inc, Rahway, NJ, and AtheroGenics Inc, Alpharetta, Ga. Dr Perrella reports no conflicts.
|
References |
|---|
|
TopIntroductionHO-1: Critical Contribution to...HO-1: Functions Beyond Iron...HO-1: Protection Against...Induction of HO-1Prolonged and High Levels...Proposed Mode of ProtectionUnifying MechanismsReferences |
|---|
1. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968; 61: 748–755.
2. Yoshida T, Takahashi S, Kikuchi G. Partial purification and reconstitution of the heme oxygenase system from pig spleen microsomes. J Biochem. 1974; 75: 1187–1191.
3. Maines MD, Kappas A. Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P-450 is not essential for this enzyme activity. Proc Natl Acad Sci U S A. 1974; 71: 4293–4297.
4. Liu Y, Ortiz de Montellano PR. Reaction intermediates and single turnover rate constants for the oxidation of heme by human heme oxygenase-1. J Biol Chem. 2000; 275: 5297–5307.
5. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987; 235: 1043–1046.
6. Abraham NG, Kappas A. Heme oxygenase and the cardiovascular-renal system. Free Radic Biol Med. 2005; 39: 1–25.[Medline] [Order article via Infotrieve]
7. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev. 2006; 86: 583–650.
8. Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem. 1994; 40: 18–23.
9. Yet SF, Layne MD, Liu X, Chen YH, Ith B, Sibinga NE, Perrella MA. Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling. FASEB J. 2003; 17: 1759–1761.
10. Duckers HJ, Boehm M, True AL, Yet S-F, San H, Park JL, Webb RC, Lee M-E, Nable GJ, Nabel EG. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001; 7: 693–698.[CrossRef][Medline] [Order article via Infotrieve]
11. Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, Ith B, Melo LG, Zhang L, Ingwall JS, Dzau VJ, Lee ME, Perrella MA. Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res. 2001; 89: 168–173.
12. Koury MJ, Ponka P. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004; 24: 105–131.[CrossRef][Medline] [Order article via Infotrieve]
13. Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A. 1997; 94: 10919–10924.
14. Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK, Tysoe SA, Wolosker H, Baranano DE, Dore S, Poss KD, Snyder SH. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999; 1: 152–157.[CrossRef][Medline] [Order article via Infotrieve]
15. Vile GF, Tyrrell RM. Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin. J Biol Chem. 1993; 268: 14678–14681.
16. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004; 117: 285–297.[CrossRef][Medline] [Order article via Infotrieve]
17. Khan ZA, Farhangkhoee H, Barbin YP, Adams PC, Chakrabarti S. Glucose-induced regulation of novel iron transporters in vascular endothelial cell dysfunction. Free Radic Res. 2005; 39: 1203–1210.[CrossRef][Medline] [Order article via Infotrieve]
18. Nanami M, Ookawara T, Otaki Y, Ito K, Moriguchi R, Miyagawa K, Hasuike Y, Izumi M, Eguchi H, Suzuki K, Nakanishi T. Tumor necrosis factor--induced iron sequestration and oxidative stress in human endothelial cells. Arterioscler Thromb Vasc Biol. 2005; 25: 2495–2501.
19. Wang LJ, Lee TS, Lee FY, Pai RC, Chau LY. Expression of heme oxygenase-1 in atherosclerotic lesions. Am J Pathol. 1998; 152: 711–720.[Abstract]
20. Minqin R, Watt F, Tan BKH, Halliwell B. Correlation of iron and zinc levels with lesion depth in newly formed atherosclerotic lesions. Free Radic Biol Med. 2003; 34: 746–752.[CrossRef][Medline] [Order article via Infotrieve]
21. Converso DP, Taille C, Carreras MC, Jaitovich A, Poderoso JJ, Boczkowski J. HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. FASEB J. 2006; 20: E382–E492.
22. Ishizaka N, de Leon H, Laursen JB, Fukui T, Wilcox JN, De Keulenaer G, Griendling KK, Alexander RW. Angiotensin II-induced hypertension increases heme oxygenase-1 expression in rat aorta. Circulation. 1997; 96: 1923–1929.
23. Chen XL, Varner SE, Rao AS, Grey JY, Thomas S, Cook CK, Wasserman MA, Medford RM, Jaiswal AK, Kunsch C. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells: a novel anti-inflammatory mechanism. J Biol Chem. 2003; 278: 703–711.
24. Sumi D, Ignarro LJ. Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide. Diabetes. 2004; 53: 1841–1850.
25. Favatier F, Polla BS. Tobacco-smoke-inducible human haem oxygenase-1 gene expression: role of distinct transcription factors and reactive oxygen intermediates. Biochem J. 2001; 353: 475–482.[CrossRef][Medline] [Order article via Infotrieve]
26. Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest. 1997; 100: 1209–1216.[Medline] [Order article via Infotrieve]
27. Keaney JF Jr, Larson MG, Vasan RS, Wilson PW, Lipinska I, Corey D, Massaro JM, Sutherland P, Vita JA, Benjamin EJ. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham study. Arterioscler Thromb Vasc Biol. 2003; 23: 434–439.
28. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999; 103: 129–135.[Medline] [Order article via Infotrieve]
29. Exner M, Minar E, Wagner O, Schillinger M. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med. 2004; 37: 1097–1104.[CrossRef][Medline] [Order article via Infotrieve]
30. Chen YH, Lin SJ, Lin MW, Tsai HL, Kuo SS, Chen JW, Charng MJ, Wu TC, Chen LC, Ding YA, Pan WH, Jou YS, Chau L. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet. 2002; 111: 1–8.[CrossRef][Medline] [Order article via Infotrieve]
31. Kaneda H, Ohno M, Taguchi J, Togo M, Hashimoto H, Ogasawara K, Aizawa T, Ishizaka N, Nagai R. Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol. 2002; 22: 1680–1685.
32. Endler G, Exner M, Schillinger M, Marculescu R, Sunder-Plassmann R, Raith M, Jordanova N, Wojta J, Mannhalter C, Wagner O, Huber K. A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with increased bilirubin and HDL levels but not with coronary artery disease. Thromb Haemost. 2004; 91: 155–161.[Medline] [Order article via Infotrieve]
33. Chen YH, Lin SJ, Lin MW, Chen LC, Yo MH, Chen JW, Lin SJ. Heme oxygenase-1 promoter microsatellite polymorphism is associated with angiographic restenosis after coronary stenting. Eur Heart J. 2004; 25: 39–47.
34. Ono K, Goto Y, Takagi S, Baba S, Tago N, Nonogi H, Iwai N. A promoter variant of the heme oxygenase-1 gene may reduce the incidence of ischemic heart disease in Japanese. Atherosclerosis. 2004; 173: 315–319.[CrossRef][Medline] [Order article via Infotrieve]
35. Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004; 84: 1381–1478.
36. Ishikawa K, Sugawara D, Goto J, Watanabe Y, Kawamura K, Shiomi M, Itabe H, Maruyama Y. Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits. Circulation. 2001; 104: 1831–1836.
37. Ishikawa K, Sugawara D, Wang X, Suzuki K, Itabe H, Maruyama Y, Lusis AJ. Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL- receptor knockout mice. Circ Res. 2001; 88: 506–512.
38. Juan SH, Lee TS, Tseng KW, Liou JY, Shyue SK, Wu KK, Chau LY. Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2001; 104: 1519–1525.
39. Grundemar L, Ny L. Pitfalls using metalloporphyrins in carbon monoxide research. Trends Pharmacol Sci. 1997; 18: 193–195.[Medline] [Order article via Infotrieve]
40. Tulis DA, Durante W, Liu X, Evans AJ, Peyton KJ, Schafer AI. Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation. Circulation. 2001; 104: 2710–2715.
41. Pellacani A, Wiesel P, Sharma A, Foster LC, Huggins GS, Yet SF, Perrella MA. Induction of heme oxygenase-1 during endotoxemia is downregulated by transforming growth factor-beta1. Circ Res. 1998; 83: 396–403.
42. Ahmad Z, Salim M, Maines MD. Human biliverdin reductase is a leucine zipper-like DNA-binding protein and functions in transcriptional activation of heme oxygenase-1 by oxidative stress. J Biol Chem. 2002; 277: 9226–9232.
43. Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9–19.[Abstract]
44. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo MM, Yamamoto M, Igarashi K. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 2002; 21: 5216–5224.[CrossRef][Medline] [Order article via Infotrieve]
45. Sun J, Brand M, Zenke Y, Tashiro S, Groudine M, Igarashi K. Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc Natl Acad Sci U S A. 2004; 101: 1461–1466.
46. Omura S, Suzuki H, Toyofuku M, Ozono R, Kohno N, Igarashi K. Effects of genetic ablation of Bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury. Genes Cells. 2005; 10: 277–285.
47. Chung SW, Chen YH, Perrella MA. Role of Ets-2 in the regulation of heme oxygenase-1 by endotoxin. J Biol Chem. 2005; 280: 4578–4584.
48. Shibahara S, Müller RM, Taguchi H. Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem. 1987; 262: 12889–12892.
49. Liu XM, Peyton KJ, Ensenat D, Wang H, Schafer AI, Alam J, Durante W. Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle: role in cell survival. J Biol Chem. 2005; 280: 872–877.
50. Deng YM, Wu BJ, Witting PK, Stocker R. Probucol protects against smooth muscle cell proliferation by upregulating heme oxygenase-1. Circulation. 2004; 110: 1855–1860.
51. Keyse SM, Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci U S A. 1989; 86: 99–103.
52. Agarwal A, Shiraishi F, Visner GA, Nick HS. Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells. J Am Soc Nephrol. 1998; 9: 1990–1997.[Abstract]
53. Kronke G, Bochkov VN, Huber J, Gruber F, Bluml S, Furnkranz A, Kadl A, Binder BR, Leitinger N. Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein. J Biol Chem. 2003; 278: 51006–51014.
54. Agarwal A, Balla J, Balla G, Croatt AJ, Vercellotti GM, Nath KA. Renal tubular epithelial cells mimic endothelial cells upon exposure to oxidized LDL. Am J Physiol Renal Fluid Electrolyte Physiol. 1996; 271: F814–F823.
55. Mostert V, Hill KE, Burk RF. Loss of activity of the selenoenzyme thioredoxin reductase causes induction of hepatic heme oxygenase-1. FEBS Lett. 2003; 541: 85–88.[CrossRef][Medline] [Order article via Infotrieve]
56. Grosser N, Hemmerle A, Berndt G, Erdmann K, Hinkelmann U, Schürger S, Wijayanti N, Immenschuh S, Schröder H. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med. 2004; 37: 2064–2071.[CrossRef][Medline] [Order article via Infotrieve]
57. Lee TS, Chang CC, Zhu Y, Shyy JY. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation. 2004; 110: 1296–1302.
58. Hsu M, Muchova L, Morioka I, Wong RJ, Schröder H, Stevenson DK. Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo. Biochem Biophys Res Commun. 2006; 343: 738–744.[Medline] [Order article via Infotrieve]
59. Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res. 1995; 76: 412–417.
60. Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest. 1996; 98: 2277–2283.[Medline] [Order article via Infotrieve]
61. Visner GA, Lu F, Zhou H, Liu J, Kazemfar K, Agarwal A. Rapamycin induces heme oxygenase-1 in human pulmonary vascular cells: implications in the antiproliferative response to rapamycin. Circulation. 2003; 107: 911–916.
62. Zhou H, Liu H, Porvasnik SL, Terada N, Agarwal A, Cheng Y, Visner GA. Heme oxygenase-1 mediates the protective effects of rapamycin in monocrotaline-induced pulmonary hypertension. Lab Invest. 2006; 86: 62–71.[CrossRef][Medline] [Order article via Infotrieve]
63. Choi BM, Kim YM, Jeong YR, Pae HO, Song CE, Park JE, Ahn YK, Chung HT. Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells. Biochem Biophys Res Commun. 2004; 321: 132–137.[CrossRef][Medline] [Order article via Infotrieve]
64. Motterlini R, Hidalgo A, Sammut I, Shah KA, Mohammed S, Srai K, Green CJ. A precursor of the nitric oxide donor SIN-1 modulates the stress protein heme oxygenase-1 in rat liver. Biochem Biophys Res Commun. 1996; 225: 167–172.[CrossRef][Medline] [Order article via Infotrieve]
65. Marquis JC, Demple B. Complex genetic response of human cells to sublethal levels of pure nitric oxide. Cancer Res. 1998; 58: 3435–3440.
66. Immenschuh S, Schröder H. Heme oxygenase-1 and cardiovascular disease. Histol Histopathol. 2006; 21: 679–685.[Medline] [Order article via Infotrieve]
67. Grosser N, Abate A, Oberle S, Vreman HJ, Dennery PA, Becker JC, Pohle T, Seidman DS, Schröder H. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun. 2003; 308: 956–960.[CrossRef][Medline] [Order article via Infotrieve]
68. Sawayama Y, Shimizu C, Maeda N, Tatsukawa M, Kinukawa N, Koyanagi S, Kashiwagi S, Hayashi J. Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia: Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiol. 2002; 39: 610–616.
69. Tardif JC, Gregoire J, Schwartz L, Title L, Laramee L, Reeves F, Lesperance J, Bourassa MG, L’Allier PL, Glass M, Lambert J, Guertin MC. Effects of AGI-1067 and probucol after percutaneous coronary interventions. Circulation. 2003; 107: 552–558.
70. Tardif J-C, Côté G, Lespérance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, de Guise P. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med. 1997; 337: 365–372.
71. Witting PK, Pettersson K, Letters J, Stocker R. Site-specific anti-atherogenic effect of probucol in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20: e26–e33.
72. Schneider JE, Berk BC, Gravanis MB, Santoian EC, Cipolla GD, Tarazona N, Lassegue B, King SB 3rd. Probucol decreases neointimal formation in a swine model of coronary artery balloon injury: a possible role for antioxidants in restenosis. Circulation. 1993; 88: 628–637.
73. Wu BJ, Kathir K, Witting PK, Beck K, Choy K, Li C, Croft KD, Mori TA, Tanous D, Adams MR, Lau AK, Stocker R. Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging. J Exp Med. 2006; 203: 1117–1127.
74. Lau AK, Leichtweis SB, Hume P, Mashima R, Hou JY, Chaufour X, Wilkinson B, Hunt NH, Celermajer DS, Stocker R. Probucol promotes functional reendothelialization in balloon-injured rabbit aortas. Circulation. 2003; 107: 2031–2036.
75. Walldius G, U. E., Olsson AG, Bergstrand L, Hådell K, Johansson J, Kaijser L, Lassvik C, Mölgaard J, Nilsson S, Schäfer-Elinder L, Stenport G, Holme I. The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol. 1994; 74: 875–883.[CrossRef][Medline] [Order article via Infotrieve]
76. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003; 24: 449–455.[CrossRef][Medline] [Order article via Infotrieve]
77. Bach FH. Heme oxygenase-1: a therapeutic amplification funnel. FASEB J. 2005; 19: 1216–1219.
78. Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003; 43: 233–260.[CrossRef][Medline] [Order article via Infotrieve]
79. Johnson TR, Mann BE, Clark JE, Foresti R, Green CJ, Motterlini R. Metal carbonyls: a new class of pharmaceuticals? Angew Chem Int Ed Engl. 2003; 42: 3722–37229.[CrossRef]
80. Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, Motterlini R. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res. 2003; 93: e2–e8.[CrossRef][Medline] [Order article via Infotrieve]
81. Nakao A, Murase N, Ho C, Toyokawa H, Billiar TR, Kanno S. Biliverdin administration prevents the formation of intimal hyperplasia induced by vascular injury. Circulation. 2005; 112: 587–591.
82. Öllinger R, Bilban M, Erat A, Froio A, McDaid J, Tyagi S, Csizmadia E, Graça-Souza AV, Liloia A, Soares MP, Otterbein LE, Usheva A, Yamashita K, Bach FH. Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation. 2005; 112: 1030–1039.
83. McDonagh AF. Biliverdin, immune-mediated liver injury, and the Gigo effect. Hepatology. 2005; 41: 680–681.[CrossRef][Medline] [Order article via Infotrieve]
84. Sassa S, Kappas A, Bernstein SE, Alvares AP. Heme biosynthesis and drug metabolism in mice with hereditary hemolytic anemia: heme oxygenase induction as an adaptive response for maintaining cytochrome P-450 in chronic hemolysis. J Biol Chem. 1979; 254: 729–735.
85. Melo LG, Agrawal R, Zhang L, Rezvani M, Mangi AA, Ehsan A, Griese DP, Dell’Acqua G, Mann MJ, Oyama J, Yet SF, Layne MD, Perrella MA, Dzau VJ. Gene therapy strategy for long-term myocardial protection using adeno- associated virus–mediated delivery of heme oxygenase gene. Circulation. 2002; 105: 602–607.
86. Minamino T, Christou H, Hsieh C-M, Liu Y, Dhawan V, Abraham NG, Perrella MA, Mitsialis SA, Kourembanas S. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci U S A. 2001; 98: 8798–8803.
87. Morita T, Imai T, Sugiyama T, Katayama S, Yoshino G. Heme oxygenase-1 in vascular smooth muscle cells counteracts cardiovascular damage induced by angiotensin II. Curr Neurovasc Res. 2005; 2: 113–120.[CrossRef][Medline] [Order article via Infotrieve]
88. Haider A, Olszanecki R, Gryglewski R, Schwartzman ML, Lianos E, Kappas A, Nasjletti A, Abraham NG. Regulation of cyclooxygenase by the heme-heme oxygenase system in microvessel endothelial cells. J Pharmacol Exp Ther. 2002; 300: 188–194.
89. Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, Csizmadia E, Tyagi S, Akamatsu Y, Flavell RJ, Billiar TR, Tzeng E, Bach FH, Choi AM, Soares MP. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 2003; 9: 183–190.[CrossRef][Medline] [Order article via Infotrieve]
90. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000; 6: 422–428.[CrossRef][Medline] [Order article via Infotrieve]
91. Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med. 2002; 8: 240–246.[CrossRef][Medline] [Order article via Infotrieve]
92. Bilban M, Bach FH, Otterbein SL, Ifedigbo E, de Costa d’Avila J, Esterbauer H, Chin BY, Usheva A, Robson SC, Wagner O, Otterbein LE. Carbon monoxide orchestrates a protective response through PPAR. Immunity. 2006; 24: 601–610.[CrossRef][Medline]
[Order article via Infotrieve]
93. Brüne B, Ullrich V. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol. 1987; 32: 497–504.[Abstract]
94. Peng L, Mundada L, Stomel JM, Liu JJ, Sun J, Yet SF, Fay WP. Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis. Antioxid Redox Signal. 2004; 6: 729–735.[CrossRef][Medline] [Order article via Infotrieve]
95. Fujita T, Toda K, Karimova A, Yan SF, Naka Y, Yet SF, Pinsky DJ. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Nat Med. 2001; 7: 598–604.[CrossRef][Medline] [Order article via Infotrieve]
96. Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med. 2000; 192: 1015–1026.
97. Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui T-Y, Bach FH. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol. 2004; 172: 3553–3563.
98. Morita T, Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. J Clin Invest. 1995; 96: 2676–2682.[Medline] [Order article via Infotrieve]
99. Morita T, Mitsialis SA, Koike H, Liu Y, Kourembanas S. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem. 1997; 272: 32804–32809.
100. Wu L, Cao K, Lu Y, Wang R. Different mechanisms underlying the stimulation of KCa channels by nitric oxide and carbon monoxide. J Clin Invest. 2002; 110: 691–700.[CrossRef][Medline] [Order article via Infotrieve]
101. Liu X-M, Chapman GB, Wang H, Durante W. Adenovirus-mediated heme oxygenase-1 gene expression stimulates apoptosis in vascular smooth muscle cells. Circulation. 2002; 105: 79–84.
102. Sacerdoti D, Escalante B, Abraham NG, McGiff JC, Levere RD, Schwartzman ML. Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats. Science. 1989; 243: 388–390.
103. Graser T, Vedernikov YP, Li DS. Study on the mechanism of carbon monoxide induced endothelium-independent relaxation in porcine coronary artery and vein. Biomed Biochim Acta. 1990; 49: 293–296.[Medline] [Order article via Infotrieve]
104. Foresti R, Hammad J, Clark JE, Johnson TR, Mann BE, Friebe A, Green CJ, Motterlini R. Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br J Pharmacol. 2004; 142: 453–460.[CrossRef][Medline] [Order article via Infotrieve]
105. Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991; 28: 52–61.[Medline] [Order article via Infotrieve]
106. Zakhary R, Gaine SP, Dinerman JL, Ruat M, Flavahan NA, Snyder SH. Heme oxygenase 2: endothelial and neuronal localization and role in endothelium-dependent relaxation. Proc Natl Acad Sci U S A. 1996; 93: 795–798.
107. Johnson FK, Johnson RA. Carbon monoxide promotes endothelium-dependent constriction of isolated gracilis muscle arterioles. Am J Physiol Regul Integr Comp Physiol. 2003; 285: R536–R541.
108. Imai T, Morita T, Shindo T, Nagai R, Yazaki Y, Kurihara H, Suematsu M, Katayama S. Vascular smooth muscle cell–directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide–induced vasodilation in mice. Circ Res. 2001; 89: 55–62.
109. Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U S A. 1997; 94: 10925–10930.
110. Hori R, Kashiba M, Toma T, Yachie A, Goda N, Makino N, Soejima A, Nagasawa T, Nakabayashi K, Suematsu M. Gene transfection of H25A mutant heme oxygenase-1 protects cells against hydroperoxide-induced cytotoxicity. J Biol Chem. 2002; 277: 10712–10718.
111. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM. Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem. 1992; 267: 18148–18153.
112. Dennery PA, Visner G, Weng YH, Nguyen X, Lu F, Zander D, Yang G. Resistance to hyperoxia with heme oxygenase-1 disruption: role of iron. Free Radic Biol Med. 2003; 34: 124–133.[CrossRef][Medline] [Order article via Infotrieve]
113. Stocker R. Antioxidant activities of bile pigments. Antioxid Redox Signal. 2004; 6: 841–849.[Medline] [Order article via Infotrieve]
114. Clark JE, Foresti R, Green CJ, Motterlini R. Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J. 2000; 348: 615–619.[CrossRef][Medline] [Order article via Infotrieve]
115. Dennery PA, McDonagh AF, Spitz DR, Rodgers PA, Stevenson DK. Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic Biol Med. 1995; 19: 395–404.[CrossRef][Medline] [Order article via Infotrieve]
116. Shi W, Haberland ME, Jien ML, Shih DM, Lusis AJ. Endothelial responses to oxidized lipoproteins determine genetic susceptibility to atherosclerosis in mice. Circulation. 2000; 102: 75–81.
117. Terry CM, Clikeman JA, Hoidal JR, Callahan KS. Effect of tumor necrosis factor- and interleukin-1 on heme oxygenase-1 expression in human endothelial cells. Am J Physiol Heart Circ Physiol. 1998; 274: H883–H891.
118. Kacimi R, Chentoufi J, Honbo N, Long CS, Karliner JS. Hypoxia differentially regulates stress proteins in cultured cardiomyocytes: role of the p38 stress-activated kinase signaling cascade, and relation to cytoprotection. Cardiovasc Res. 2000; 46: 139–150.
119. Motterlini R, Foresti R, Intaglietta M, Winslow RM. NO-mediated activation of heme oxygenase: endogenous cytoprotection against oxidative stress to endothelium. Am J Physiol Heart Circ Physiol. 1996; 270: H107–H114.
120. Tulis DA, Durante W, Peyton KJ, Evans AJ, Schafer AI. Heme oxygenase-1 attenuates vascular remodeling following balloon injury in rat carotid arteries. Atherosclerosis. 2001; 155: 113–122.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  F. Ali, N. S. Ali, A. Bauer, J. J. Boyle, S. S. Hamdulay, D. O. Haskard, A. M. Randi, and J. C. Mason PPAR{delta} and PGC1{alpha} act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress Cardiovasc Res, December 3, 2009; (2009) cvp365v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Wu, R. G. Midwinter, C. Cassano, K. Beck, Y. Wang, D. Changsiri, J. R. Gamble, and R. Stocker Heme Oxygenase-1 Increases Endothelial Progenitor Cells Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1537 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Li, Y. Guo, Q. Ou, C. Cui, W.-J. Wu, W. Tan, X. Zhu, L. B. Lanceta, S. K. Sanganalmath, B. Dawn, et al. Gene Transfer of Inducible Nitric Oxide Synthase Affords Cardioprotection by Upregulating Heme Oxygenase-1 Via a Nuclear Factor-{kappa}B-Dependent Pathway Circulation, September 29, 2009; 120(13): 1222 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, V. Rubio, M. W. Lieberman, and Z.-Z. Shi OLA1, an Obg-like ATPase, suppresses antioxidant response via nontranscriptional mechanisms PNAS, September 8, 2009; 106(36): 15356 - 15361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ali, M. Zakkar, K. Karu, E. A. Lidington, S. S. Hamdulay, J. J. Boyle, M. Zloh, A. Bauer, D. O. Haskard, P. C. Evans, et al. Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow J. Biol. Chem., July 10, 2009; 284(28): 18882 - 18892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zarjou, V. Jeney, P. Arosio, M. Poli, P. Antal-Szalmas, A. Agarwal, G. Balla, and J. Balla Ferritin Prevents Calcification and Osteoblastic Differentiation of Vascular Smooth Muscle Cells J. Am. Soc. Nephrol., June 1, 2009; 20(6): 1254 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nicolai, M. Li, D. H. Kim, S. J. Peterson, L. Vanella, V. Positano, A. Gastaldelli, R. Rezzani, L. F. Rodella, G. Drummond, et al. Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats Hypertension, March 1, 2009; 53(3): 508 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Almolki, A. Guenegou, S. Golda, L. Boyer, M. Benallaoua, N. Amara, R. Bachoual, C. Martin, F. Rannou, S. Lanone, et al. Heme Oxygenase-1 Prevents Airway Mucus Hypersecretion Induced by Cigarette Smoke in Rodents and Humans Am. J. Pathol., October 1, 2008; 173(4): 981 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Idriss, A. D. Blann, and G. Y.H. Lip Hemoxygenase-1 in Cardiovascular Disease J. Am. Coll. Cardiol., September 16, 2008; 52(12): 971 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Peterson, G. Drummond, D. H. Kim, M. Li, A. L. Kruger, S. Ikehara, and N. G. Abraham L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice J. Lipid Res., August 1, 2008; 49(8): 1658 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Evans, F. Niemevz, G. Buldain, and P. O. de Montellano Isoporphyrin Intermediate in Heme Oxygenase Catalysis: OXIDATION OF {alpha}-MESO-PHENYLHEME J. Biol. Chem., July 11, 2008; 283(28): 19530 - 19539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-K. Jyrkkanen, E. Kansanen, M. Inkala, A. M. Kivela, H. Hurttila, S. E. Heinonen, G. Goldsteins, S. Jauhiainen, S. Tiainen, H. Makkonen, et al. Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo Circ. Res., July 3, 2008; 103(1): e1 - e9. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Kivela, E. Kansanen, H.-K. Jyrkkanen, T. Nurmi, S. Yla-Herttuala, and A.-L. Levonen Enterolactone Induces Heme Oxygenase-1 Expression through Nuclear Factor-E2-Related Factor 2 Activation in Endothelial Cells J. Nutr., July 1, 2008; 138(7): 1263 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tongers, J.-M. Knapp, M. Korf, T. Kempf, A. Limbourg, F. P. Limbourg, Z. Li, D. Fraccarollo, J. Bauersachs, X. Han, et al. Haeme oxygenase promotes progenitor cell mobilization, neovascularization, and functional recovery after critical hindlimb ischaemia in mice Cardiovasc Res, May 1, 2008; 78(2): 294 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-L. Levonen, E. Vahakangas, J. K. Koponen, and S. Yla-Herttuala Antioxidant Gene Therapy for Cardiovascular Disease: Current Status and Future Perspectives Circulation, April 22, 2008; 117(16): 2142 - 2150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dooley, S. Y. Low, A. Holmes, A. G. Kidane, D. J. Abraham, C. M. Black, and K. R. Bruckdorfer Nitric oxide synthase expression and activity in the tight-skin mouse model of fibrosis Rheumatology, March 1, 2008; 47(3): 272 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dulak, J. Deshane, A. Jozkowicz, and A. Agarwal Heme Oxygenase-1 and Carbon Monoxide in Vascular Pathobiology: Focus on Angiogenesis Circulation, January 15, 2008; 117(2): 231 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rokosh Heme Egr-1: New Partners in Atherosclerotic Progression? Circ. Res., January 4, 2008; 102(1): 6 - 8. [Full Text] [PDF]
|
|
|
|
|
|
T. S. Perlstein, R. L. Pande, J. A. Beckman, and M. A. Creager Serum Total Bilirubin Level and Prevalent Lower-Extremity Peripheral Arterial Disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 166 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. True, M. Olive, M. Boehm, H. San, R. J. Westrick, N. Raghavachari, X. Xu, E. G. Lynn, M. N. Sack, P. J. Munson, et al. Heme Oxygenase-1 Deficiency Accelerates Formation of Arterial Thrombosis Through Oxidative Damage to the Endothelium, Which Is Rescued by Inhaled Carbon Monoxide Circ. Res., October 26, 2007; 101(9): 893 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pugazhenthi, L. Akhov, G. Selvaraj, M. Wang, and J. Alam Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse beta-cells Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E645 - E655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Gleissner, N. Leitinger, and K. Ley Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis Hypertension, August 1, 2007; 50(2): 276 - 283. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||