This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Förstermann, U. Articles by Münzel, T. Search for Related Content PubMed PubMed Citation Articles by Förstermann, U. Articles by Münzel, T. Related Collections Pathophysiology Gene regulation Oxidant stress Endothelium/vascular type/nitric oxide

(Circulation. 2006;113:1708-1714.)
© 2006 American Heart Association, Inc.

Basic Science for Clinicians

Endothelial Nitric Oxide Synthase in Vascular Disease

From Marvel to Menace

Ulrich Förstermann, MD, PhD; Thomas Münzel, MD

From the Departments of Pharmacology (U.F.) and Internal Medicine II (Cardiology) (T.M.), Johannes Gutenberg University Hospitals, Mainz, Germany.

Correspondence to Ulrich Förstermann, MD, PhD, Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. E-mail ulrich.forstermann{at}uni-mainz.de

	Abstract

Top Abstract Introduction Vascular Protection by eNOS... Conclusions References

 
Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO·. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate L-arginine, and the essential cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH₄), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O₂·^–) reacts avidly with vascular NO· to form peroxynitrite (ONOO^–). The cofactor BH₄ is highly sensitive to oxidation by ONOO^–. Diminished levels of BH₄ promote O₂·^– production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH₄ has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH₄ levels as well.

Key Words: endothelium • arteriosclerosis • endothelium-derived factors • nitric oxide synthase • risk factors

	Introduction

Top Abstract Introduction Vascular Protection by eNOS... Conclusions References

 
The roughly 10¹⁴ endothelial cells of our vasculature protect us against atherosclerosis and thrombosis. A major weapon of endothelial cells to fight vascular disease is endothelial nitric oxide synthase (eNOS), an enzyme that generates the vasoprotective molecule nitric oxide (NO·). However, many of us unintentionally mistreat our endothelial cells. We expose them to risk factors such as cigarette smoke, high blood pressure, high glucose, or high lipids. Despite this abuse, our endothelium bears with us for some time, tries to maintain NO· production, and preserves vascular protection. However, the risk factors lead to excess production of superoxide (O₂·^–; ie, they produce oxidative stress). O₂·^– reacts with NO· to form peroxynitrite, and vascular protection slowly vanishes. But that is only the beginning of the calamity. Our eNOS now enters into a vicious biochemical cycle. It changes its enzymology, starts making peroxynitrite (ONOO^–) itself, and eventually becomes an enzyme that generates only O₂·^–. This brief review discusses how and when this happens and how it may be prevented.

	Vascular Protection by eNOS-Derived NO·

Top Abstract Introduction Vascular Protection by eNOS... Conclusions References

 
eNOS, the predominant NOS isoform in the vasculature, is responsible for most of the NO· produced in this tissue.¹ Vascular NO· dilates all types of blood vessels by stimulating soluble guanylyl cyclase and increasing cyclic guanosine monophosphate (cGMP) in smooth muscle cells.¹ NO· released toward the vascular lumen is a potent inhibitor of platelet aggregation and adhesion. NO· also can inhibit leukocyte adhesion to the vessel wall either by interfering with the ability of the leukocyte adhesion molecule CD11/CD18 to form an adhesive bond with the endothelial cell surface or by suppressing CD11/CD18 expression on leukocytes. White cell adherence is an early event in the development of atherosclerosis; therefore, NO· may protect against the onset of atherogenesis. Furthermore, NO· has been shown to inhibit DNA synthesis, mitogenesis, and proliferation of vascular smooth muscle cells. The inhibition of platelet aggregation and adhesion protects smooth muscle from exposure to platelet-derived growth factor(s). Therefore, NO· also prevents a later step in atherogenesis, fibrous plaque formation. Based on the combination of those effects, endothelial NO· probably represents the most important antiatherogenic defense principle in the vasculature.¹

NOS Structure and Structure-Related Enzymology
All NOS isoforms are modular enzymes. In intact NOS, a C-terminal reductase domain (which binds nicotinamide adenine dinucleotide phosphate [NADPH], flavin mononucleotide [FMN], and flavin adenine dinucleotide [FAD]) is linked to the N-terminal oxygenase domain of the other monomer (Figure 1). As shown in Figure 1C, the oxygenase domain carries a prosthetic heme group. The oxygenase domain also binds (6R-)5,6,7,8-tetrahydrobiopterin (BH₄), molecular oxygen, and the substrate L-arginine.¹ Sequences located near the cysteine ligand of the heme are apparently also involved in L-arginine and BH₄ binding (Figure 2A). All 3 NOS isoforms possess a zinc-thiolate cluster formed by a zinc ion that is tetrahedrally coordinated to 2 CXXXXC motifs (1 contributed by each monomer) at the NOS dimer interface² (Figure 2A). Chemical removal of zinc from NOS or the possibility of expressing a zinc-deficient NOS that remained catalytically active demonstrated that the zinc in NOS is structural rather than catalytic. All NOS isozymes catalyze flavin-mediated electron transfer from the C-terminally bound NADPH to the heme on the N terminus. Calmodulin (on calcium-induced binding) increases the rate of electron transfer from NADPH via the reductase domain flavins to the heme center (Figures 1B and 1C). At the heme, the electrons are used to reduce and activate O₂. To synthesize NO·, the enzyme needs to cycle twice. In a first step, NOS hydroxylates L-arginine to N-hydroxy-L-arginine (which remains largely bound to the enzyme). In a second step, NOS oxidizes N-hydroxy-L-arginine to L-citrulline and NO· (Figure 1C).³ In human eNOS, Cys99, which is part of the zinc-thiolate cluster, is thought to represent (or largely contribute to) the binding site for BH₄; zinc itself does not contribute to BH₄ binding. Mutation of the homologous Cys331 in nNOS to alanine (C331A) led to an enzyme that lost its binding affinity for BH₄ and became catalytically incompetent.⁴

View larger version (32K): [in this window] [in a new window]   Figure 1. A, Basic structure of eNOS and scheme of NOS catalysis. All NOS enzymes are synthesized as monomers. Each subunit consists of a reductase domain and an oxygenase domain. Monomers and even isolated reductase domains are able to transfer electrons from NADPH to the flavins FAD and FMN and have a limited capacity to reduce molecular oxygen to O2·–. Monomers and isolated reductase domains can bind calmodulin (CaM), which stimulates the electron transfer within the reductase domain. However, monomers are unable to bind the cofactor BH4 or the substrate L-arginine and cannot catalyze NO· production. B, The presence of heme allows NOS dimerization; in fact, heme is the only cofactor that is absolutely required for the formation of active NOS dimers. Heme also is essential for the interaction between reductase and oxygenase domains and for the interdomain electron transfer from the flavins to the heme of the opposite monomer. NADPH oxidation rates are significantly enhanced in heme-containing substrate-free NOS dimers compared with monomers, consistent with a more effective O2·– production. C, When sufficient substrate L-arginine and cofactor BH4 are present, intact NOS dimers couple their heme and O2 reduction to the synthesis of NO·. L-Citrulline is formed as the byproduct; N-hydroxy-L-arginine is an intermediate in the reaction.

View larger version (42K): [in this window] [in a new window]   Figure 2. A, A closer look at the dimer interface of human eNOS. All NOS isoforms contain a zinc-thiolate cluster formed by a zinc ion coordinated in a tetrahedral conformation with pairs of CXXXXC motifs at the dimer interface. This site not only binds Zn but also is of major importance for the binding of the cofactor BH4 and the substrate L-arginine. Interestingly, there is evidence for a mutual enhancement of BH4 and L-arginine binding, which may be of therapeutic relevance in vivo. In human eNOS, Cys99 is essential for BH4 binding; a Cys99Ala mutation reduces BH4 binding by 90% and cuts catalytic activity to 20% (even at very high concentrations of added BH4). Electron transfer from the reductase domain (1) enables NOS ferric (Fe3+) heme to bind O2 and form a ferrous (Fe2+)-dioxy species. This species may receive a second electron preferentially from BH4 (or from the reductase domain) (2). This activates the oxygen and allows the catalysis of L-arginine hydroxylation. Recent observations indeed suggest that BH4 acts as a 1-electron donor during reductive oxygen activation at the eNOS (rather than an allosteric activator). The nature of the resulting oxidized BH4 has been identified by electron paramagnetic resonance as the trihydrobiopterin radical (BH3·) or trihydropterin radical cation protonated at N5 (BH3· H+). The BH3· radical (or radical cation) can be recycled to BH4 by NOS itself (using an electron supplied by the flavins). Alternatively, there is evidence that ascorbate (which is present in cells in millimolar concentrations) can reduce the BH3· radical back to BH4. This function of ascorbate can explain its stimulation of eNOS activity. The BH3. radical also can be disproportionate to the quinoid 6,7-[8H]-H2-biopterin, which can be reduced by ascorbate back to BH4. BH4 is likely to play a redox role in the second reaction cycle, ie, the conversion of N-hydroxy-L-arginine to NO. B, Significant O2·– production will occur when the effective concentrations of L-arginine fall below levels required to saturate the enzyme. In these circumstances, eNOS catalyzes the uncoupled reduction of O2, leading to the production of O2·– (and/or H2O2). C, Oxidative stress is associated with endothelial dysfunction. Indeed, a BH4 depletion of isolated arteries or rats in vivo produced endothelial dysfunction in a short period of time. Conversely, BH4 is efficient in restoring endothelial dysfunction in a surprisingly wide range of experimental and clinical settings. Mechanistically, O2·– derived from the NADPH oxidases and/or xanthine oxidase (see above) may combine with NO· formed by a still-functional eNOS. This would lead to increased formation of ONOO–. ONOO– has been shown to oxidize BH4 to biologically inactive products such as BH3· radical or 6,7-[8H]-H2-biopterin (BH2), thereby leading to an uncoupling of NOS. D, In addition to BH4 deficiency, another mechanism has been postulated by which ONOO– can lead to dysfunction of eNOS, namely the oxidation of the zinc-thiolate cluster of eNOS, which leads to a loss of zinc and a potential destabilization of the eNOS dimer. Consequently, O2·– production would increase at the expense of a decreased NO production. However, this mechanism may be closely related to BH4 deficiency because Cys99 of eNOS also is part of the BH4 binding site. AscH indicates ascorbic acid; Asc·, ascorbate radical.

O₂·^– Generation by eNOS and Enzyme Dimerization
The flow of electrons within NOS is tightly regulated. If disturbed, the ferrous-dioxygen complex dissociates, and O₂·^– is generated from the oxygenase domain instead of NO· (Figures 2B through 2D). This is referred to as NOS uncoupling.

In the recent literature, NOS-catalyzed reduction of molecular oxygen to O₂·^– has been attributed to the failure of the enzyme to form dimers. Indeed, it has been shown that monomers of NOS and even isolated reductase domains are sufficient for O₂·^– production (Figure 1A). However, the NADPH oxidase activity of such enzyme fragments is limited; the dimeric form has much higher enzymatic activity (Figure 1B). Studies with inhibitors of dimerization on inducible NOS have suggested that once a dimer is formed, there is little or no significant return to the monomer.⁵ Most probably, this also applies to eNOS. Thus, uncoupling of oxygen reduction from NO· formation is unlikely to go along with significant monomerization of the enzyme in vivo.

Cardiovascular Risk Factors Cause Endothelial Dysfunction: Potential Mechanisms Involved
In the presence of cardiovascular risk factors, endothelial dysfunction frequently is encountered. Several molecular defects could account for reductions in endothelium-dependent vascular relaxation.

Endothelial dysfunction could be due to decreased eNOS expression. However, several studies have shown that cardiovascular risk factors are associated with an increase rather than a decrease in eNOS expression.⁶ The increased expression of eNOS in vascular disease is likely to be a consequence of an excess production of H₂O₂. H₂O₂, the dismutation product of O₂·^–, can increase eNOS expression through transcriptional and posttranscriptional mechanisms.⁷

On the other hand, an accelerated degradation of NO· (by its reaction with O₂·^–) is likely to occur in vascular disease. NO· and O₂·^– react avidly to form ONOO^–, which in turn leads to eNOS uncoupling and enzyme dysfunction (see below and Figures 2C, 2D, and 3).

View larger version (40K): [in this window] [in a new window]   Figure 3. Potential mechanisms by which cardiovascular risk factors lead to endothelial dysfunction. In many types of vascular disease, NADPH oxidases and eNOS are upregulated in parallel. Their respective products rapidly recombine to form ONOO–. This oxidizes BH4, the essential cofactor of eNOS, and/or produces oxidative damage to the zinc-thiolate cluster of eNOS. Thus, O2 reduction by eNOS is uncoupled from NO· formation, and a functional NOS is converted into a dysfunctional O2·– -generating enzyme that contributes to vascular oxidative stress.

Cardiovascular Risk Factors and Vascular Disease Are Associated With Increased Levels of Reactive Oxygen Species
Cardiovascular risk factors increase the expression and/or activity of NADPH oxidases (NOX) in the vascular wall, thereby enhancing the production of reactive oxygen species (ROS). Evidence for an activation of NOX has been provided in animal models of hypertension such as angiotensin II infusion⁸ or spontaneously hypertensive rats (SHRs)⁹ and models of diabetes mellitus.¹⁰ In addition, experimental hypercholesterolemia is associated with an activation of NOX.¹¹ In atherosclerotic arteries, increased expression of gp91phox (Nox2) and Nox4 has been observed¹² (Figure 3). The stimulating effects of angiotensin II on the activity of these enzymes suggests that an activated (local or systemic) renin-angiotensin system can cause vascular dysfunction.¹³ In addition, in hypercholesterolemia, local renin-angiotensin systems may be activated.¹⁴ In vessels from hypercholesterolemic animals¹⁵ and in platelets from hypercholesterolemic patients,¹⁶ the AT₁ receptor has been found to be upregulated.

Xanthine oxidase is another potential source of ROS in vascular disease. The enzyme readily donates electrons to molecular oxygen, thereby producing O₂·^– and H₂O₂. Oxypurinol, an inhibitor of xanthine oxidase, has been shown to reduce O₂·^– production and improve endothelium-dependent vascular relaxations to acetylcholine in blood vessels from hyperlipidemic animals.¹⁷ This suggests a contribution of xanthine oxidase to endothelial dysfunction in early hypercholesterolemia. Unlike NOX, however, the general importance of xanthine oxidase for endothelial dysfunction is uncertain. Whereas some investigators reported an improvement in endothelial dysfunction in hypercholesterolemic and diabetic patients with xanthine oxidase inhibitors,¹⁸ other failed to show an effect with allopurinol.¹⁹

Uncoupled eNOS Contributes to Endothelial Dysfunction
Evidence for uncoupling of eNOS has been obtained in endothelial cells treated with low-density lipoprotein (LDL),²⁰ in ONOO^–-treated rat aorta,²¹ and in isolated blood vessels from animals with pathophysiological conditions such as SHRs,²² stroke-prone SHRs,²³ angiotensin II–induced hypertension,²⁴ hypertension induced with the mineralocorticoid deoxycorticosterone acetate (DOCA),²⁵ streptozotocin-induced diabetes,¹⁰ or nitroglycerin tolerance.²⁶

Importantly, NOS uncoupling has also been seen in patients with endothelial dysfunction resulting from hypercholesterolemia,²⁷ diabetes mellitus,²⁸ or essential hypertension²⁹; in chronic smokers³⁰; and in nitroglycerin-treated patients.³¹

This raises questions about the pathophysiological mechanism(s) leading to eNOS uncoupling in vascular disease. There is a growing body of evidence that vascular NOX plays a crucial role in the phenomenon of eNOS uncoupling in humans. The important hint came from experiments with NOX (p47phox)-knockout animals.²⁵ DOCA-salt–treated hypertensive mice showed an increased production of vascular ROS. This was significantly reduced by the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), demonstrating a marked contribution of uncoupled eNOS to oxidative stress in vascular tissue. p47phox-knockout animals showed much less oxidative stress on DOCA-salt treatment, and levels of ROS could no longer be reduced with L-NAME.²⁵

Potential Role of L-Arginine in eNOS Uncoupling
Beneficial effects of L-arginine supplementation have been documented in both animal studies and humans under pathophysiological conditions such as hypercholesterolemia and hypertension.^32–34 This raises the question as to whether L-arginine concentrations can become critical as a substrate in vivo (Figure 2B). At first glance, this appears unlikely. The K_M of eNOS for L-arginine is 3 µmol/L³⁵; normal L-arginine plasma concentrations are 100 µmol/L (even in pathophysiology, they hardly fall below 60 µmol/L); and there is up to a 10-fold accumulation of L-arginine within cells.³⁶ In addition, human endothelial cells can effectively recycle L-citrulline to L-arginine and can obtain L-arginine from protein breakdown.³⁷

On the other hand, endothelial cells express arginases that can compete with eNOS for substrate and, if highly expressed, "starve" eNOS. Arginase exists in 2 isoforms; in human endothelial cells, arginase II seems to be the predominant isozyme.^38,39 Upregulated expression and activity of arginase II have been found in corpus cavernosum of diabetic individuals⁴⁰ and in endothelium from the lung of pulmonary hypertensive patients.⁴¹ Evidence for a role of increased enzymatic activity of arginase in endothelial dysfunction also has been provided in animal models of cardiovascular disease such as aging,⁴² atherosclerosis,³⁸ endothelial dysfunction after ischemia-reperfusion,⁴³ and hypertension induced by aortic coarctation or high salt.^44,45 In apolipoprotein E–knockout mice, the expression of arginase II was unchanged compared with wild-type mice, but the activity of the enzyme was markedly increased.³⁸ Similarly, in human umbilical vein endothelial cells, arginase II enzymatic activity was enhanced after an 18- to 24-hour exposure to thrombin³⁸ or a 24-hour stimulation with inflammatory cytokines.³⁹

Thus, a relative L-arginine deficiency in the vicinity of eNOS caused by excessive arginase activity is conceivable and could explain part of the beneficial effects of L-arginine supplementation. Effects of supplemental L-arginine also could be due to local competition with the endogenous eNOS inhibitor asymmetric dimethyl-L-arginine (ADMA)⁴⁶ (see below).

However, also nonsubstrate effects of L-arginine can contribute to these effects. These include potential direct radical scavenging properties of the guanidino nitrogen group or the cooperativeness between the L-arginine and BH₄ binding sites on NOS⁴ (Figure 2A).

Potential Role of ADMA in eNOS Uncoupling
ADMA represents a novel independent predictor for all-cause cardiovascular mortality. The activities (not the expression) of both protein arginine N-methyltransferase (PRMT, type I)⁴⁷ and the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH)⁴⁸ are redox sensitive. In cultured endothelial cells, rat models, and humans, oxidative stress has been shown to increase the activity of PRMT(s) and decrease that of DDAH, thereby leading to increased ADMA concentrations.^46–48 Thus, an increased production of ROS could be the reason for increased ADMA levels. Elevated ADMA may inhibit NO· synthesis by eNOS or could even uncouple the enzyme, which would enhance oxidative stress.⁴⁶ However, it remains to be established whether ADMA concentrations reached in vivo (even in pathophysiology) are sufficient to effectively interact with eNOS.

Role of BH₄ in eNOS Uncoupling
NO· and L-citrulline production by eNOS in endothelial cells correlates closely with the intracellular concentration of BH₄,⁴⁹ and supplementation with BH₄ is capable of correcting eNOS dysfunction in several types of pathophysiology. In isolated aortas from prehypertensive SHRs, BH₄ supplementation diminished the NOS-dependent generation of O₂·^–.²² Administration of BH₄ restored endothelial function in animal models of diabetes⁵⁰ and insulin resistance,⁵¹ as well as in patients with hypercholesterolemia,²⁷ diabetes mellitus,²⁸ and essential hypertension²⁹ and in chronic smokers.³⁰

Intracellular BH₄ levels depend on the balance of its de novo synthesis and its oxidation/degradation. BH₄ is one of the most potent naturally occurring reducing agents. It is therefore reasonable to hypothesize that oxidative stress may lead to excessive oxidation and depletion of BH₄^21,52 (Figure 2C). Thus, oxidation of BH₄ may be the common cause of eNOS dysfunction in vascular pathophysiology. In agreement with this concept, BH₄ levels have been found to be decreased in the aorta of insulin-resistant rats,⁵³ in plasma of SHRs compared with age-matched Wistar-Kyoto rats,⁵⁴ in aorta of hypercholesterolemic apolipoprotein E–knockout mice,²¹ and in DOCA-salt–treated hypertensive rats.²⁵

It is important to note that particularly ONOO^–, the direct reaction product of NO· and O₂·^–, is able to oxidize BH₄. Recently published studies revealed that ONOO^– oxidizes BH₄ to the BH₃· radical, which can be re-reduced to BH₄ by NOS itself or by appropriate chemical reducing agents such as ascorbic acid (vitamin C)^55,56 (Figure 2A). Thus, the improvement in endothelial function seen with infusions of vitamin C^57–59 may involve mechanisms beyond mere protection of NO from inactivation by free oxygen radicals. Because of an enhanced regeneration of BH₄,^55,56 ascorbic acid can "recouple" eNOS and enhance its enzymatic activity.

Improvement in Endothelial Dysfunction by Folic Acid
Folic acid has proved effective in reversing endothelial dysfunction in animal models of cardiovascular disease and in patients with cardiovascular risk factors.^60–62 Recent studies have indicated that folates possess stabilizing effects on the heme-containing oxygenase domain of eNOS.⁶³ First, folates may rescue or stabilize BH₄ by stimulating the endogenous regeneration of quinoid BH₂ to BH₄. This can recouple the eNOS enzyme, thereby increasing NO production. Second, folates as reduced pteridines, have potent antioxidant properties per se and can directly scavenge the O₂·^– produced by an uncoupled eNOS. Third, folates may interact with the pteridine-binding site in NOS. This can enhance the binding of BH₄, leading to a facilitated electron transfer from the reductase domain or BH₄ itself to the catalytic heme center.

Oxidation of the Zinc-Thiolate Cluster in eNOS May Lead to Enzyme Uncoupling
Zou et al⁶⁴ have put forth an alternative concept potentially explaining eNOS uncoupling. They showed that the exposure of the isolated enzyme to ONOO^– leads to a disruption of the zinc-thiolate cluster, resulting in an uncoupling of the enzyme (Figure 2D). BH₄ was oxidized at concentrations 10- to 100-fold higher than those needed to disrupt the zinc-thiolate complex. From these findings, the authors suggested that the principal mechanism of uncoupling is the oxidation of the zinc-thiolate center rather than BH₄ oxidation.⁶⁴ However, it should be kept in mind that Cys99 in the thiolate center of eNOS is also essential for BH₄ binding (Figure 2A); its oxidation would damage the BH₄ binding site (Figure 2D) with similar consequences for the enzyme as oxidation of the cofactor itself. In addition, it is not clear whether a loss of zinc from eNOS ever occurs in intact cells in vivo.

Potential Clinical Interventions to Restore Normal eNOS Function
On the basis of the pathophysiology mentioned above, there are several possible approaches to restore eNOS functionality (ie, recouple eNOS) in the clinical situation. These include the intra-arterial infusion of the eNOS cofactor BH₄ as demonstrated by studies in chronic smokers,³⁰ diabetics,²⁸ hypercholesterolemic patients,²⁷ and hypertensive individuals.²⁹

Folic acid increases intracellular BH₄ levels and has been used successfully to restore endothelial function in patients with hypercholesterolemia,⁶⁰ diabetes mellitus,⁶¹ or hyperhomocysteinemia.⁶² Folic acid also prevented or reversed eNOS dysfunction in nitroglycerin-treated patients³¹ and in healthy volunteers with postprandial endothelial dysfunction.⁶⁵

In addition, infusions of high doses of vitamin C have been found to improve endothelial function acutely.^57–59 The exact mechanism of action of ascorbic acid is unknown, but as detailed above, vitamin C also is likely to recouple eNOS (Figure 2A).

	Conclusions

Top Abstract Introduction Vascular Protection by eNOS... Conclusions References

 
Oxidative stress and endothelial dysfunction in the coronary and peripheral circulation have important prognostic implications for subsequent cardiovascular events. As detailed here, an increased production of ROS by uncoupled eNOS contributes markedly to this pathophysiology (Figure 3).

	Acknowledgments

 
Disclosures

None.

	References

Top Abstract Introduction Vascular Protection by eNOS... Conclusions References

 
1. Förstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isozymes: characterization, purification, molecular cloning, and functions. Hypertension. 1994; 23: 1121–1131.[Abstract/Free Full Text]

2. Raman CS, Li H, Martasek P, Kral V, Masters BS, Poulos TL. Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell. 1998; 95: 939–950.[CrossRef][Medline] [Order article via Infotrieve]

3. Stuehr D, Pou S, Rosen GM. Oxygen reduction by nitric-oxide synthases. J Biol Chem. 2001; 276: 14533–14536.[Free Full Text]

4. Martasek P, Miller RT, Liu Q, Roman LJ, Salerno JC, Migita CT, Raman CS, Gross SS, Ikeda-Saito M, Masters BS. The C331A mutant of neuronal nitric-oxide synthase is defective in arginine binding. J Biol Chem. 1998; 273: 34799–34805.[Abstract/Free Full Text]

5. McMillan K, Adler M, Auld DS, Baldwin JJ, Blasko E, Browne LJ, Chelsky D, Davey D, Dolle RE, Eagen KA, Erickson S, Feldman RI, Glaser CB, Mallari C, Morrissey MM, Ohlmeyer MH, Pan G, Parkinson JF, Phillips GB, Polokoff MA, Sigal NH, Vergona R, Whitlow M, Young TA, Devlin JJ. Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc Natl Acad Sci U S A. 2000; 97: 1506–1511.[Abstract/Free Full Text]

6. Li H, Wallerath T, Münzel T, Förstermann U. Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. Nitric Oxide Biol Chem. 2002; 7: 149–164.[CrossRef][Medline] [Order article via Infotrieve]

7. Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG. Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res. 2000; 86: 347–354.[Abstract/Free Full Text]

8. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996; 97: 1916–1923.[Medline] [Order article via Infotrieve]

9. Li H, Witte K, August M, Brausch I, Gödtel-Armbrust U, Habermeier A, Closs EI, Oelze M, Münzel T, Förstermann U. Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol. In press.

10. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Förstermann U, Münzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001; 88: E14–E22.[Medline] [Order article via Infotrieve]

11. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm M, Meinertz T, Munzel T. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation. 1999; 99: 2027–2033.[Abstract/Free Full Text]

12. Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK. Superoxide production and expression of Nox family proteins in human atherosclerosis. Circulation. 2002; 105: 1429–1435.[Abstract/Free Full Text]

13. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.[Abstract/Free Full Text]

14. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996; 94: 2756–2767.[Abstract/Free Full Text]

15. Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of L-arginine availability. Circulation. 2000; 101: 1261–1266.[Abstract/Free Full Text]

16. Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M. Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation. 1999; 100: 2131–2134.[Abstract/Free Full Text]

17. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993; 91: 2546–2551.[Medline] [Order article via Infotrieve]

18. Cardillo C, Kilcoyne CM, Cannon RO, 3rd, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension. 1997; 30: 57–63.[Abstract/Free Full Text]

19. O’Driscoll JG, Green DJ, Rankin JM, Taylor RR. Nitric oxide-dependent endothelial function is unaffected by allopurinol in hypercholesterolaemic subjects. Clin Exp Pharmacol Physiol. 1999; 26: 779–783.[CrossRef][Medline] [Order article via Infotrieve]

20. Pritchard KA, Jr., Groszek L, Smalley DM, Sessa WC, Wu M, Villalon P, Wolin MS, Stemerman MB. Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res. 1995; 77: 510–518.[Abstract/Free Full Text]

21. Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation. 2001; 103: 1282–1288.[Abstract/Free Full Text]

22. Cosentino F, Luscher TF. Tetrahydrobiopterin and endothelial function. Eur Heart J. 1998; 19 (suppl G): G3–G8.[Medline] [Order article via Infotrieve]

23. Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF, Hamilton CA. Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. Hypertension. 1999; 33: 1353–1358.[Abstract/Free Full Text]

24. Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, Munzel T. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res. 2002; 90: E58–E65.[CrossRef][Medline] [Order article via Infotrieve]

25. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003; 111: 1201–1209.[CrossRef][Medline] [Order article via Infotrieve]

26. Münzel T, Li H, Mollnau H, Hink U, Matheis E, Hartmann M, Oelze M, Skatchkov M, Warnholtz A, Duncker L, Meinertz T, Förstermann U. Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability. Circ Res. 2000; 86: E7–E12.[Medline] [Order article via Infotrieve]

27. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest. 1997; 99: 41–46.[Medline] [Order article via Infotrieve]

28. Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia. 2000; 43: 1435–1438.[CrossRef][Medline] [Order article via Infotrieve]

29. Higashi Y, Sasaki S, Nakagawa K, Fukuda Y, Matsuura H, Oshima T, Chayama K. Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals. Am J Hypertens. 2002; 15: 326–332.[CrossRef][Medline] [Order article via Infotrieve]

30. Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Munzel T. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase. Circ Res. 2000; 86: E36–E41.[Medline] [Order article via Infotrieve]

31. Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation. 2001; 104: 1119–1123.[Abstract/Free Full Text]

32. Imaizumi T, Hirooka Y, Masaki H, Harada S, Momohara M, Tagawa T, Takeshita A. Effects of L-arginine on forearm vessels and responses to acetylcholine. Hypertension. 1992; 20: 511–517.[Abstract/Free Full Text]

33. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991; 338: 1546–1550.[CrossRef][Medline] [Order article via Infotrieve]

34. Rossitch E, Alexander E, Black PM, Cooke JP. L-Arginine normalizes endothelial function in cerebral vessels from hypercholesterolemic rabbits. J Clin Invest. 1991; 87: 1295–1299.[Medline] [Order article via Infotrieve]

35. Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, Murad F. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A. 1991; 88: 10480–10484.[Abstract/Free Full Text]

36. Closs EI, Scheld JS, Sharafi M, Forstermann U. Substrate supply for nitric-oxide synthase in macrophages and endothelial cells: role of cationic amino acid transporters. Mol Pharmacol. 2000; 57: 68–74.[Abstract/Free Full Text]

37. Simon A, Plies L, Habermeier A, Martine U, Reining M, Closs EI. Role of neutral amino acid transport and protein breakdown for substrate supply of nitric oxide synthase in human endothelial cells. Circ Res. 2003; 93: 813–820.[Abstract/Free Full Text]

38. Ming XF, Barandier C, Viswambharan H, Kwak BR, Mach F, Mazzolai L, Hayoz D, Ruffieux J, Rusconi S, Montani JP, Yang Z. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation. 2004; 110: 3708–3714.[Abstract/Free Full Text]

39. Bachetti T, Comini L, Francolini G, Bastianon D, Valetti B, Cadei M, Grigolato P, Suzuki H, Finazzi D, Albertini A, Curello S, Ferrari R. Arginase pathway in human endothelial cells in pathophysiological conditions. J Mol Cell Cardiol. 2004; 37: 515–523.[CrossRef][Medline] [Order article via Infotrieve]

40. Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC. Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction. Biochem Biophys Res Commun. 2001; 283: 923–927.[CrossRef][Medline] [Order article via Infotrieve]

41. Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL, Jennings C, Dweik RA, Arroliga AC, Erzurum SC. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J. 2004; 18: 1746–1748.[Abstract/Free Full Text]

42. Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation. 2003; 108: 2000–2006.[Abstract/Free Full Text]

43. Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L. Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J. 2003; 17: 2328–2330.[Abstract/Free Full Text]

44. Zhang C, Hein TW, Wang W, Miller MW, Fossum TW, McDonald MM, Humphrey JD, Kuo L. Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles. Hypertension. 2004; 44: 935–943.[Abstract/Free Full Text]

45. Johnson FK, Johnson RA, Peyton KJ, Durante W. Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension. Am J Physiol Regul Integr Comp Physiol. 2005; 288: R1057–R1062.[Abstract/Free Full Text]

46. Sydow K, Munzel T. ADMA and oxidative stress. Atheroscler Suppl. 2003; 4: 41–51.[Medline] [Order article via Infotrieve]

47. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002; 106: 987–992.[Abstract/Free Full Text]

48. Böger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Böger SM. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res. 2000; 87: 99–105.[Abstract/Free Full Text]

49. Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Schmidt K, Weiss G, Wachter H. Pteridine biosynthesis in human endothelial cells: impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem. 1993; 268: 1842–1846.[Abstract/Free Full Text]

50. Pieper GM. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol. 1997; 29: 8–15.[CrossRef][Medline] [Order article via Infotrieve]

51. Shinozaki K, Nishio Y, Okamura T, Yoshida Y, Maegawa H, Kojima H, Masada M, Toda N, Kikkawa R, Kashiwagi A. Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ Res. 2000; 87: 566–573.[Abstract/Free Full Text]

52. Milstien S, Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem Biophys Res Commun. 1999; 263: 681–684.[CrossRef][Medline] [Order article via Infotrieve]

53. Shinozaki K, Kashiwagi A, Nishio Y, Okamura T, Yoshida Y, Masada M, Toda N, Kikkawa R. Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O₂^– imbalance in insulin-resistant rat aorta. Diabetes. 1999; 48: 2437–2445.[Abstract]

54. Hong H-J, Hsiao G, Cheng T-H, Yen M-H. Supplementation with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension. 2001; 38: 1044–1048.[Abstract/Free Full Text]

55. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003; 278: 22546–22554.[Abstract/Free Full Text]

56. Werner ER, Gorren AC, Heller R, Werner-Felmayer G, Mayer B. Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects. Exp Biol Med. 2003; 228: 1291–1302.[Abstract/Free Full Text]

57. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001; 104: 2673–2678.[Abstract/Free Full Text]

58. Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation. 1996; 94: 6–9.[Abstract/Free Full Text]

59. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1996; 97: 22–28.[Medline] [Order article via Infotrieve]

60. Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation. 1998; 97: 237–241.[Abstract/Free Full Text]

61. van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ. Impaired NO-dependent vasodilation in patients with type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia. 2002; 45: 1004–1010.[CrossRef][Medline] [Order article via Infotrieve]

62. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999; 34: 2002–2006.[Abstract/Free Full Text]

63. Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002; 22: 6–13.[Abstract/Free Full Text]

64. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002; 109: 817–826.[CrossRef][Medline] [Order article via Infotrieve]

65. Wilmink HW, Stroes ES, Erkelens WD, Gerritsen WB, Wever R, Banga JD, Rabelink TJ. Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2000; 20: 185–188.[Abstract/Free Full Text]

This article has been cited by other articles:

				C. Marchesi, T. Ebrahimian, O. Angulo, P. Paradis, and E. L. Schiffrin Endothelial Nitric Oxide Synthase Uncoupling and Perivascular Adipose Oxidative Stress and Inflammation Contribute to Vascular Dysfunction in a Rodent Model of Metabolic Syndrome Hypertension, December 1, 2009; 54(6): 1384 - 1392. [Abstract] [Full Text] [PDF]

				J. Herrmann, L. O. Lerman, and A. Lerman On to the road to degradation: atherosclerosis and the proteasome Cardiovasc Res, November 14, 2009; (2009) cvp333v2. [Abstract] [Full Text] [PDF]

				E. H. Heiss, D. Schachner, E. R. Werner, and V. M. Dirsch Active NF-E2-related Factor (Nrf2) Contributes to Keep Endothelial NO Synthase (eNOS) in the Coupled State: ROLE OF REACTIVE OXYGEN SPECIES (ROS), eNOS, AND HEME OXYGENASE (HO-1) LEVELS J. Biol. Chem., November 13, 2009; 284(46): 31579 - 31586. [Abstract] [Full Text] [PDF]

				Y.-M. Yang, A. Huang, G. Kaley, and D. Sun eNOS uncoupling and endothelial dysfunction in aged vessels Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1829 - H1836. [Abstract] [Full Text] [PDF]

				Z. Lu, I. Scott, B. R. Webster, and M. N. Sack The Emerging Characterization of Lysine Residue Deacetylation on the Modulation of Mitochondrial Function and Cardiovascular Biology Circ. Res., October 23, 2009; 105(9): 830 - 841. [Abstract] [Full Text] [PDF]

				T. Munzel and T. Gori Nebivolol The Somewhat-Different beta-Adrenergic Receptor Blocker. J. Am. Coll. Cardiol., October 13, 2009; 54(16): 1491 - 1499. [Abstract] [Full Text] [PDF]

				K. Stangl and V. Stangl The ubiquitin proteasome pathway and endothelial (dys)function Cardiovasc Res, October 13, 2009; (2009) cvp315v2. [Abstract] [Full Text] [PDF]

				J. H. Kim, L. J. Bugaj, Y. J. Oh, T. J. Bivalacqua, S. Ryoo, K. G. Soucy, L. Santhanam, A. Webb, A. Camara, G. Sikka, et al. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats J Appl Physiol, October 1, 2009; 107(4): 1249 - 1257. [Abstract] [Full Text] [PDF]

				V. A. Rufanova, V. F. Pozdnev, E. I. Kalenikova, A. B. Postnikov, A. N. Storozhilova, V. P. Masenko, O. A. Gomazkov, O. S. Medvedev, and N. A. Medvedeva Endothelin-Converting Enzyme Inhibition in the Rat Model of Acute Heart Failure: Heart Function and Neurohormonal Activation Experimental Biology and Medicine, October 1, 2009; 234(10): 1201 - 1211. [Abstract] [Full Text] [PDF]

				J. Gutkowska, T. L. Broderick, D. Bogdan, D. Wang, J.-M. Lavoie, and M. Jankowski Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy J. Physiol., October 1, 2009; 587(19): 4725 - 4736. [Abstract] [Full Text] [PDF]

				J. Xu and M.-H. Zou Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction Circulation, September 29, 2009; 120(13): 1266 - 1286. [Full Text] [PDF]

				Z. Ying, T. Kampfrath, G. Thurston, B. Farrar, M. Lippmann, A. Wang, Q. Sun, L. C. Chen, and S. Rajagopalan Ambient Particulates Alter Vascular Function through Induction of Reactive Oxygen and Nitrogen Species Toxicol. Sci., September 1, 2009; 111(1): 80 - 88. [Abstract] [Full Text] [PDF]

				E. Yamamoto, K. Kataoka, Y.-F. Dong, T. Nakamura, M. Fukuda, Y. Tokutomi, S. Matsuba, H. Nako, N. Nakagata, T. Kaneko, et al. Aliskiren Enhances the Protective Effects of Valsartan Against Cardiovascular and Renal Injury in Endothelial Nitric Oxide Synthase-Deficient Mice Hypertension, September 1, 2009; 54(3): 633 - 638. [Abstract] [Full Text] [PDF]

				S. Wang, J. Xu, P. Song, B. Viollet, and M.-H. Zou In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I Diabetes, August 1, 2009; 58(8): 1893 - 1901. [Abstract] [Full Text] [PDF]

				T. R. Nurkiewicz, D. W. Porter, A. F. Hubbs, S. Stone, B. T. Chen, D. G. Frazer, M. A. Boegehold, and V. Castranova Pulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling Toxicol. Sci., July 1, 2009; 110(1): 191 - 203. [Abstract] [Full Text] [PDF]

				E. Shuto, Y. Taketani, R. Tanaka, N. Harada, M. Isshiki, M. Sato, K. Nashiki, K. Amo, H. Yamamoto, Y. Higashi, et al. Dietary Phosphorus Acutely Impairs Endothelial Function J. Am. Soc. Nephrol., July 1, 2009; 20(7): 1504 - 1512. [Abstract] [Full Text] [PDF]

				M. Sharma, Z. Zhou, H. Miura, A. Papapetropoulos, E. T. McCarthy, R. Sharma, V. J. Savin, and E. A. Lianos ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1386 - F1395. [Abstract] [Full Text] [PDF]

				Y. Wang, Y. Huang, K. S.L. Lam, Y. Li, W. T. Wong, H. Ye, C.-W. Lau, P. M. Vanhoutte, and A. Xu Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase Cardiovasc Res, June 1, 2009; 82(3): 484 - 492. [Abstract] [Full Text] [PDF]

				J. Bauersachs and J. D. Widder Tetrahydrobiopterin, Endothelial Nitric Oxide Synthase, and Mitochondrial Function in the Heart Hypertension, June 1, 2009; 53(6): 907 - 908. [Full Text] [PDF]

				A. F. Ceylan-Isik, K. K. Guo, E. C. Carlson, J. R. Privratsky, S.-J. Liao, L. Cai, A. F. Chen, and J. Ren Metallothionein Abrogates GTP Cyclohydrolase I Inhibition-Induced Cardiac Contractile and Morphological Defects: Role of Mitochondrial Biogenesis Hypertension, June 1, 2009; 53(6): 1023 - 1031. [Abstract] [Full Text] [PDF]

				R. P. Weerackody, D. J. Welsh, R. M. Wadsworth, and A. J. Peacock Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1312 - H1320. [Abstract] [Full Text] [PDF]

				J. Lahdenranta, J. Hagendoorn, T. P. Padera, T. Hoshida, G. Nelson, S. Kashiwagi, R. K. Jain, and D. Fukumura Endothelial Nitric Oxide Synthase Mediates Lymphangiogenesis and Lymphatic Metastasis Cancer Res., April 1, 2009; 69(7): 2801 - 2808. [Abstract] [Full Text] [PDF]

				B. Egemnazarov, A. Sydykov, R. T. Schermuly, N. Weissmann, J.-P. Stasch, A. S. Sarybaev, W. Seeger, F. Grimminger, and H. A. Ghofrani Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L462 - L469. [Abstract] [Full Text] [PDF]

				C. Antoniades, A. S. Antonopoulos, D. Tousoulis, K. Marinou, and C. Stefanadis Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials Eur. Heart J., January 1, 2009; 30(1): 6 - 15. [Abstract] [Full Text] [PDF]

				A. Farsetti, A. Grasselli, S. Bacchetti, C. Gaetano, and M. C. Capogrossi The telomerase tale in vascular aging: regulation by estrogens and nitric oxide signaling J Appl Physiol, January 1, 2009; 106(1): 333 - 337. [Abstract] [Full Text] [PDF]

				J. M. Hughes, O. Wirth, K. Krajnak, R. Miller, S. Flavahan, D. E. Berkowitz, D. Welcome, and N. A. Flavahan Increased Oxidant Activity Mediates Vascular Dysfunction in Vibration Injury J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 223 - 230. [Abstract] [Full Text] [PDF]

				Y.-M. Lu, F. Han, N. Shioda, S. Moriguchi, Y. Shirasaki, Z.-H. Qin, and K. Fukunaga Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist Mol. Pharmacol., January 1, 2009; 75(1): 101 - 112. [Abstract] [Full Text] [PDF]

				S. Mohan, R. Konopinski, B. Yan, V. E. Centonze, and M. Natarajan High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction Am J Physiol Cell Physiol, January 1, 2009; 296(1): C182 - C192. [Abstract] [Full Text] [PDF]

				F. J. Blanco, M. T. Grande, C. Langa, B. Oujo, S. Velasco, A. Rodriguez-Barbero, E. Perez-Gomez, M. Quintanilla, J. M. Lopez-Novoa, and C. Bernabeu S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology Circ. Res., December 5, 2008; 103(12): 1383 - 1392. [Abstract] [Full Text] [PDF]

				N. Ouchi, Y. Oshima, K. Ohashi, A. Higuchi, C. Ikegami, Y. Izumiya, and K. Walsh Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism J. Biol. Chem., November 21, 2008; 283(47): 32802 - 32811. [Abstract] [Full Text] [PDF]

				Q. Sun, P. Yue, Z. Ying, A. J. Cardounel, R. D. Brook, R. Devlin, J.-S. Hwang, J. L. Zweier, L. C. Chen, and S. Rajagopalan Air Pollution Exposure Potentiates Hypertension Through Reactive Oxygen Species-Mediated Activation of Rho/ROCK Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1760 - 1766. [Abstract] [Full Text] [PDF]

				F. Moien-Afshari, S. Ghosh, S. Elmi, M. Khazaei, M. M. Rahman, N. Sallam, and I. Laher Exercise restores coronary vascular function independent of myogenic tone or hyperglycemic status in db/db mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1470 - H1480. [Abstract] [Full Text] [PDF]

				H. Li, M. Hortmann, A. Daiber, M. Oelze, M. A. Ostad, P. M. Schwarz, H. Xu, N. Xia, A. L. Kleschyov, C. Mang, et al. Cyclooxygenase 2-Selective and Nonselective Nonsteroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Up-Regulating Vascular NADPH Oxidases J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 745 - 753. [Abstract] [Full Text] [PDF]

				G. A. Wiggers, F. M. Pecanha, A. M. Briones, J. V. Perez-Giron, M. Miguel, D. V. Vassallo, V. Cachofeiro, M. J. Alonso, and M. Salaices Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1033 - H1043. [Abstract] [Full Text] [PDF]

				S. Wang, J. Xu, P. Song, Y. Wu, J. Zhang, H. Chul Choi, and M.-H. Zou Acute Inhibition of Guanosine Triphosphate Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Blood Pressure Hypertension, September 1, 2008; 52(3): 484 - 490. [Abstract] [Full Text] [PDF]

				E. Yamamoto, Y.-F. Dong, K. Kataoka, T. Yamashita, Y. Tokutomi, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Olmesartan Prevents Cardiovascular Injury and Hepatic Steatosis in Obesity and Diabetes, Accompanied by Apoptosis Signal Regulating Kinase-1 Inhibition Hypertension, September 1, 2008; 52(3): 573 - 580. [Abstract] [Full Text] [PDF]

				D. Fraccarollo, J. D. Widder, P. Galuppo, T. Thum, D. Tsikas, M. Hoffmann, H. Ruetten, G. Ertl, and J. Bauersachs Improvement in Left Ventricular Remodeling by the Endothelial Nitric Oxide Synthase Enhancer AVE9488 After Experimental Myocardial Infarction Circulation, August 19, 2008; 118(8): 818 - 827. [Abstract] [Full Text] [PDF]

				K. G. Maier Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Diabetes: Vascular Implications Vascular and Endovascular Surgery, August 1, 2008; 42(4): 305 - 313. [Abstract] [PDF]

				N. D. Vaziri Mechanisms of lead-induced hypertension and cardiovascular disease Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H454 - H465. [Abstract] [Full Text] [PDF]

				C. G. Tankersley, H. C. Champion, E. Takimoto, K. Gabrielson, D. Bedja, V. Misra, H. El-Haddad, R. Rabold, and W. Mitzner Exposure to inhaled particulate matter impairs cardiac function in senescent mice Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R252 - R263. [Abstract] [Full Text] [PDF]

				N. Sasaki, T. Yamashita, T. Takaya, M. Shinohara, R. Shiraki, M. Takeda, N. Emoto, A. Fukatsu, T. Hayashi, K. Ikemoto, et al. Augmentation of Vascular Remodeling by Uncoupled Endothelial Nitric Oxide Synthase in a Mouse Model of Diabetes Mellitus Arterioscler Thromb Vasc Biol, June 1, 2008; 28(6): 1068 - 1076. [Abstract] [Full Text] [PDF]

				E. R. Kline, D. J. Kleinhenz, B. Liang, S. Dikalov, D. M. Guidot, C. M. Hart, D. P. Jones, and R. L. Sutliff Vascular oxidative stress and nitric oxide depletion in HIV-1 transgenic rats are reversed by glutathione restoration Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2792 - H2804. [Abstract] [Full Text] [PDF]

				A. L. Moens, E. Takimoto, C. G. Tocchetti, K. Chakir, D. Bedja, G. Cormaci, E. A. Ketner, M. Majmudar, K. Gabrielson, M. K. Halushka, et al. Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin: Efficacy of Recoupling Nitric Oxide Synthase as a Therapeutic Strategy Circulation, May 20, 2008; 117(20): 2626 - 2636. [Abstract] [Full Text] [PDF]

				P. Wohlfart, H. Xu, A. Endlich, A. Habermeier, E. I. Closs, T. Hubschle, C. Mang, H. Strobel, T. Suzuki, H. Kleinert, et al. Antiatherosclerotic Effects of Small-Molecular-Weight Compounds Enhancing Endothelial Nitric-Oxide Synthase (eNOS) Expression and Preventing eNOS Uncoupling J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 370 - 379. [Abstract] [Full Text] [PDF]

				Y. Hiroi, Z. Guo, Y. Li, A. H. Beggs, and J. K. Liao Dynamic regulation of endothelial NOS mediated by competitive interaction with {alpha}-actinin-4 and calmodulin FASEB J, May 1, 2008; 22(5): 1450 - 1457. [Abstract] [Full Text] [PDF]

				S. Ryoo, G. Gupta, A. Benjo, H. K. Lim, A. Camara, G. Sikka, H. K. Lim, J. Sohi, L. Santhanam, K. Soucy, et al. Endothelial Arginase II: A Novel Target for the Treatment of Atherosclerosis Circ. Res., April 25, 2008; 102(8): 923 - 932. [Abstract] [Full Text] [PDF]

				A. L. Moens, H. C. Champion, M. J. Claeys, B. Tavazzi, P. M. Kaminski, M. S. Wolin, D. J. Borgonjon, L. Van Nassauw, A. Haile, M. Zviman, et al. High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury Circulation, April 8, 2008; 117(14): 1810 - 1819. [Abstract] [Full Text] [PDF]

				G. Li, J.-P. del Rincon, L. A. Jahn, Y. Wu, B. Gaylinn, M. O. Thorner, and Z. Liu Growth Hormone Exerts Acute Vascular Effects Independent of Systemic or Muscle Insulin-like Growth Factor I J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1379 - 1385. [Abstract] [Full Text] [PDF]

				R. Maas, E. Schwedhelm, L. Kahl, H. Li, R. Benndorf, N. Luneburg, U. Forstermann, and R. H. Boger Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide-Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia Clin. Chem., February 1, 2008; 54(2): 292 - 300. [Abstract] [Full Text] [PDF]

				R. P. Jankov, C. Kantores, J. Pan, and J. Belik Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L233 - L245. [Abstract] [Full Text] [PDF]

				E. Yamamoto, K. Kataoka, H. Shintaku, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Novel Mechanism and Role of Angiotensin II Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2569 - 2575. [Abstract] [Full Text] [PDF]

				H. K. Lim, H. K. Lim, S. Ryoo, A. Benjo, K. Shuleri, V. Miriel, E. Baraban, A. Camara, K. Soucy, D. Nyhan, et al. Mitochondrial arginase II constrains endothelial NOS-3 activity Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3317 - H3324. [Abstract] [Full Text] [PDF]

				S. Weber, D. Bernhard, R. Lukowski, P. Weinmeister, R. Worner, J. W. Wegener, N. Valtcheva, S. Feil, J. Schlossmann, F. Hofmann, et al. Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle Specific Expression of Either Isozyme Circ. Res., November 26, 2007; 101(11): 1096 - 1103. [Abstract] [Full Text] [PDF]

				C. C. Glembotski Endoplasmic Reticulum Stress in the Heart Circ. Res., November 9, 2007; 101(10): 975 - 984. [Abstract] [Full Text] [PDF]

				M. Imamura, Y. Waseda, G. V. Marinova, T. Ishibashi, S. Obayashi, A. Sasaki, A. Nagai, and H. Azuma Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R2081 - R2089. [Abstract] [Full Text] [PDF]

				J. Herrmann, A. M. Saguner, D. Versari, T. E. Peterson, A. Chade, M. Olson, L. O. Lerman, and A. Lerman Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis Circ. Res., October 26, 2007; 101(9): 865 - 874. [Abstract] [Full Text] [PDF]

				L. Genis, P. Gonzalo, A. S. Tutor, B. G. Galvez, A. Martinez-Ruiz, C. Zaragoza, S. Lamas, K. Tryggvason, S. S. Apte, and A. G. Arroyo Functional interplay between endothelial nitric oxide synthase and membrane type 1 matrix metalloproteinase in migrating endothelial cells Blood, October 15, 2007; 110(8): 2916 - 2923. [Abstract] [Full Text] [PDF]

				Y. Li and H. E. Schellhorn New Developments and Novel Therapeutic Perspectives for Vitamin C J. Nutr., October 1, 2007; 137(10): 2171 - 2184. [Abstract] [Full Text] [PDF]

				R. Schnabel and S. Blankenberg Oxidative Stress in Cardiovascular Disease: Successful Translation From Bench to Bedside? Circulation, September 18, 2007; 116(12): 1338 - 1340. [Full Text] [PDF]

				Hardev Ramandeep Singh Girn, S. Ahilathirunayagam, A. I. D. Mavor, and S. Homer-Vanniasinkam Reperfusion Syndrome: Cellular Mechanisms of Microvascular Dysfunction and Potential Therapeutic Strategies Vascular and Endovascular Surgery, September 1, 2007; 41(4): 277 - 293. [Abstract] [PDF]

				C. E. Teixeira, F. B. M. Priviero, and R. C. Webb Effects of 5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine (BAY 41-2272) on Smooth Muscle Tone, Soluble Guanylyl Cyclase Activity, and NADPH Oxidase Activity/Expression in Corpus Cavernosum from Wild-Type, Neuronal, and Endothelial Nitric-Oxide Synthase Null Mice J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1093 - 1102. [Abstract] [Full Text] [PDF]

				R. C.M. Siow and A. T. Churchman Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in Cardiovasc Res, September 1, 2007; 75(4): 659 - 668. [Abstract] [Full Text] [PDF]

				T. Yamashita, E. Yamamoto, K. Kataoka, T. Nakamura, S. Matsuba, Y. Tokutomi, Y.-F. Dong, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Apoptosis Signal-Regulating Kinase-1 Is Involved in Vascular Endothelial and Cardiac Remodeling Caused by Nitric Oxide Deficiency Hypertension, September 1, 2007; 50(3): 519 - 524. [Abstract] [Full Text] [PDF]

				J. Xu, Y. Wu, P. Song, M. Zhang, S. Wang, and M.-H. Zou Proteasome-Dependent Degradation of Guanosine 5'-Triphosphate Cyclohydrolase I Causes Tetrahydrobiopterin Deficiency in Diabetes Mellitus Circulation, August 21, 2007; 116(8): 944 - 953. [Abstract] [Full Text] [PDF]

				K. Steinkamp-Fenske, L. Bollinger, H. Xu, Y. Yao, S. Horke, U. Forstermann, and H. Li Reciprocal Regulation of Endothelial Nitric-Oxide Synthase and NADPH Oxidase by Betulinic Acid in Human Endothelial Cells J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 836 - 842. [Abstract] [Full Text] [PDF]

				L. A. Holowatz and W. L. Kenney Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1090 - H1096. [Abstract] [Full Text] [PDF]

				T. G. Neilan, S. L. Blake, F. Ichinose, M. J. Raher, E. S. Buys, D. S. Jassal, E. Furutani, T. M. Perez-Sanz, A. Graveline, S. P. Janssens, et al. Disruption of Nitric Oxide Synthase 3 Protects Against the Cardiac Injury, Dysfunction, and Mortality Induced by Doxorubicin Circulation, July 31, 2007; 116(5): 506 - 514. [Abstract] [Full Text] [PDF]

				G. Li, E. J. Barrett, M. O. Barrett, W. Cao, and Z. Liu Tumor Necrosis Factor-{alpha} Induces Insulin Resistance in Endothelial Cells via a p38 Mitogen-Activated Protein Kinase-Dependent Pathway Endocrinology, July 1, 2007; 148(7): 3356 - 3363. [Abstract] [Full Text] [PDF]

				E. S. Buys, M. J. Raher, S. L. Blake, T. G. Neilan, A. R. Graveline, J. J. Passeri, M. Llano, T. M. Perez-Sanz, F. Ichinose, S. Janssens, et al. Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H620 - H627. [Abstract] [Full Text] [PDF]

				J. Yang, C. B. Ambrosone, C.-C. Hong, J. Ahn, C. Rodriguez, M. J. Thun, and E. E. Calle Relationships between polymorphisms in NOS3 and MPO genes, cigarette smoking and risk of post-menopausal breast cancer Carcinogenesis, June 1, 2007; 28(6): 1247 - 1253. [Abstract] [Full Text] [PDF]

				X. Gao, X. Xu, S. Belmadani, Y. Park, Z. Tang, A. M. Feldman, W. M. Chilian, and C. Zhang TNF-{alpha} Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1269 - 1275. [Abstract] [Full Text] [PDF]

				L. A. Holowatz and W. L. Kenney Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans J. Physiol., June 1, 2007; 581(2): 863 - 872. [Abstract] [Full Text] [PDF]

				H. Viswambharan, J. M. Carvas, V. Antic, A. Marecic, C. Jud, C. E. Zaugg, X.-F. Ming, J.-P. Montani, U. Albrecht, and Z. Yang Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function Circulation, April 24, 2007; 115(16): 2188 - 2195. [Abstract] [Full Text] [PDF]

				S. Horke, I. Witte, P. Wilgenbus, M. Kruger, D. Strand, and U. Forstermann Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress-Induced Caspase Activation Circulation, April 17, 2007; 115(15): 2055 - 2064. [Abstract] [Full Text] [PDF]

				J. E. Deanfield, J. P. Halcox, and T. J. Rabelink Endothelial Function and Dysfunction: Testing and Clinical Relevance Circulation, March 13, 2007; 115(10): 1285 - 1295. [Full Text] [PDF]

				T. Thum, D. Fraccarollo, M. Schultheiss, S. Froese, P. Galuppo, J. D. Widder, D. Tsikas, G. Ertl, and J. Bauersachs Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes Diabetes, March 1, 2007; 56(3): 666 - 674. [Abstract] [Full Text] [PDF]

				L. J. Ignarro, M. L. Balestrieri, and C. Napoli Nutrition, physical activity, and cardiovascular disease: An update Cardiovasc Res, January 15, 2007; 73(2): 326 - 340. [Abstract] [Full Text] [PDF]

				T. M.C. Brunini, A. C. Mendes-Ribeiro, J. C. Ellory, and G. E. Mann Platelet nitric oxide synthesis in uremia and malnutrition: A role for L-arginine supplementation in vascular protection? Cardiovasc Res, January 15, 2007; 73(2): 359 - 367. [Abstract] [Full Text] [PDF]

				D. E. Berkowitz Myocyte Nitroso-Redox Imbalance in Sepsis: NO Simple Answer Circ. Res., January 5, 2007; 100(1): 1 - 4. [Full Text] [PDF]

				A. Drouin, N. Thorin-Trescases, E. Hamel, J. R. Falck, and E. Thorin Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries Cardiovasc Res, January 1, 2007; 73(1): 73 - 81. [Abstract] [Full Text] [PDF]

				A. Nohria, M. E. Grunert, Y. Rikitake, K. Noma, A. Prsic, P. Ganz, J. K. Liao, and M. A. Creager Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease Circ. Res., December 8, 2006; 99(12): 1426 - 1432. [Abstract] [Full Text] [PDF]

				S. Ryoo, C. A. Lemmon, K. G. Soucy, G. Gupta, A. R. White, D. Nyhan, A. Shoukas, L. H. Romer, and D. E. Berkowitz Oxidized Low-Density Lipoprotein-Dependent Endothelial Arginase II Activation Contributes to Impaired Nitric Oxide Signaling Circ. Res., October 27, 2006; 99(9): 951 - 960. [Abstract] [Full Text] [PDF]

				H. J. Zhao, S. Wang, H. Cheng, M.-z. Zhang, T. Takahashi, A. B. Fogo, M. D. Breyer, and R. C. Harris Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2664 - 2669. [Abstract] [Full Text] [PDF]

				S. Ryoo, L. Santhanam, D. Nyhan, and D. E. Berkowitz Response to Does Arginase Activity In Vitro Represent That In Vivo? Hypertension, October 1, 2006; 48(4): E15 - E15. [Full Text] [PDF]

				J. Bauersachs and D. Fraccarollo Endothelial NO Synthase Target of Aldosterone Hypertension, July 1, 2006; 48(1): 27 - 28. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Förstermann, U. Articles by Münzel, T. Search for Related Content PubMed PubMed Citation Articles by Förstermann, U. Articles by Münzel, T. Related Collections Pathophysiology Gene regulation Oxidant stress Endothelium/vascular type/nitric oxide