(Circulation. 2001;103:1930.)
© 2001 American Heart Association, Inc.
Editorial |
Measuring Circulating Oxidized Low-Density Lipoprotein to Evaluate Coronary Risk
From the Divisions of Cardiovascular Diseases (S.T.) and Endocrinology and Metabolism (J.L.W.), Department of Medicine, University of California at San Diego, La Jolla, Calif.
Correspondence to Joseph L. Witztum, MD, Department of Medicine, University of California at San Diego, 9500 Gilman Drive, BSB 1080, La Jolla, CA 92093-0682. E-mail jwitztum{at}ucsd.edu
Key Words: Editorials • cholesterol • coronary disease • myocardial infarction • angina
The hypothesis that oxidized LDL (ox-LDL) is necessary, if not obligatory, in the development of atherosclerotic lesions was formulated >20 years ago with the seminal observation that uptake of native LDL by macrophages did not result in foam cell formation. In contrast, uptake of ox-LDL via scavenger receptors resulted in the unregulated accumulation of lipid.1 Since then, multiple studies in experimental animal models have provided firm evidence of an important role of ox-LDL in atherogenesis. However, the role of ox-LDL in the clinical arena has not yet been established. The report in this issue of Circulation by Ehara et al,2 as well as several other studies, lends support to the idea that the oxidation of LDL is also relevant in humans and continues to move ox-LDL research from the bench to the bedside.3
There is substantial evidence that ox-LDL is present in vivo within atherosclerotic but not normal blood vessels. LDL that is extracted from human and animal atherosclerotic lesions has all of the physical, chemical, immunological, and biological properties of ox-LDL. Monoclonal antibodies to epitopes of ox-LDL immunostain animal and human atherosclerotic lesions. Products of lipid peroxidation, such as oxidized cholesterol, fatty acids, phospholipids, and isoprostanes, are found in atherosclerotic lesions and plasma. Autoantibodies to epitopes of ox-LDL, reflecting the fact that ox-LDL is very immunogenic, are found in lesions and plasma of animals and patients with various manifestations of atherosclerosis. In addition, radiolabeled oxidation-specific antibodies image ox-LDL in the artery of live animals, and plasma autoantibody titers of ox-LDL correlate with both the accumulation and depletion of arterial ox-LDL.4 5 Finally, a large number of animal studies have shown that antioxidants reduce the progression of atherosclerosis in animal models.3
When it is present in vivo, ox-LDL has a wide range of atherogenic properties, from early lesion formation to plaque rupture.6 These processes include inducing the expression of adhesion molecules on endothelial cells, monocyte chemotaxis and adhesion, cytotoxicity, upregulating inflammatory genes and growth factors, endothelial dysfunction, platelet aggregation and thrombus formation, and destabilizing plaques through several mechanisms, including increased expression of metalloproteinases.6 7
Concurrent with the experimental work on ox-LDL, pathological studies have shown that a majority of acute coronary syndromes (ACS) result from ruptured or disrupted coronary plaques.8 9 10 Several elegant studies have demonstrated that the development of human coronary atherosclerosis involves vessel remodeling, inflammation, and disruption of thin, weakened fibrous caps overlying a large pool of extracellular lipid. Because of the difficulties in obtaining access to freshly disrupted plaques in patients and the lack of techniques to image these lesions easily, a deficiency of knowledge exists regarding the contents of these lipid pools. However, several post mortem studies have shown that oxidized cholesterol, cholesterol esters, phospholipids, and their breakdown products are present within this lipid gruel in substantial quantities.11 12 13 Presumably, this oxidized lipid material is derived, in part, from necrotic foam-cells rich in ox-LDL that have released their contents into the extracellular space.
It is generally believed that "fully oxidized LDL" does not exist in the circulation. Blood is rich in a variety of antioxidants. Even if ox-LDL entered the circulation in minute quantities, it would be rapidly cleared by the reticuloendothelial system, particularly in the liver.14 15 In addition, both animals and patients with atherosclerosis have preexisting circulating autoantibodies to ox-LDL that could rapidly remove any ox-LDL present. In contrast, circulating minimally modified LDL (MM-LDL), in which oxidative modification has not been sufficient to cause changes recognized by scavenger receptors, was clearly described by Avagaro et al16 and Sevanian et al.17 Subsequently, several groups reported evidence for the presence of oxidation-specific epitopes on plasma LDL, presumably such MM-LDL.18 19 20 21 22
In their report, Ehara et al2 also measured levels of oxidation-specific epitopes on plasma LDL (eg, MM-LDL) in several subsets of patients with different manifestations of coronary artery disease (CAD), using a sandwich ELISA with the murine monoclonal antibody DLH3.2 19 This antibody recognizes oxidized phosphatidylcholine, including adducts with proteins that are not apoB.23 They observed that plasma levels of ox-LDL were significantly elevated in the patients with CAD compared with a control group. In addition, they showed that the ox-LDL levels correlated with the severity of the clinical presentation, ie, the patients with acute myocardial infarction (AMI) had the highest levels, followed by those with unstable angina and then those with stable angina. Impressively, their work was complemented by immunocytochemical staining with DLH3 for epitopes of ox-LDL in coronary atherectomy specimens (from a different cohort of patients), which confirmed the presence of this epitope of ox-LDL.
Although the average measurement of ox-LDL discriminated patients from controls, the measurements would have distinguished only 7 of the 45 AMI patients from the 45 patients with unstable angina. These data suggest that at their present stage of development, such measurements of epitopes of ox-LDL may not yet be sufficiently robust to be used alone to discriminate the risk of acute coronary events in individual patients. However, combining these measurements of ox-LDL epitopes with other lipid and inflammatory markers may ultimately lead to additional insights into risk and diagnosis of plaque instability.
Ehara et al2
estimated that the ox-LDL in the AMI patients was only 0.25% of the
total LDL.2 Several other
studies have also attempted to quantify circulating ox-LDL, and they
have measured levels from 0.001% in normal patients (using
DLH3)24 to 
5% in
patients with AMI (using different monoclonal antibodies to
malondialdehyde [MDA]-LDL [eg, LDL particles containing the
oxidation-epitope MDA-lysine] and copper-oxidized
LDL).20 22
However, there are several key caveats concerning the accuracy of these
measurements. These include the extent of modification and
reproducibility of the reference ox-LDL preparations that are used as
standards for these assays, the fact that only one epitope is measured
in these assays whereas potentially many epitopes may exist on any one
individual LDL, and the fact that different populations of ox-LDL may
exist. The only way to be certain of the amount of a particular epitope
that is quantitated is to ensure that the reference standard has the
same extent of oxidation on LDL as the measured LDL. The quantitation
of ox-LDL will be improved when the epitopes are better delineated and
the reference standard can be a pure preparation of the epitope. In
addition, a practical limitation of the method used by Ehara et
al2 is the need to isolate
the LDL by density ultracentrifugation and to remove other
apoB-containing lipoproteins which, although more precise in evaluating
LDL-specific associated oxidation, is impractical for performing this
outside of an investigational arena.
The work from the laboratory of Holvoet et al,20 21 22 who used immunological techniques to measure circulating levels of ox-LDL and MDA-LDL, also supports the fact that LDL containing oxidation-specific epitopes seems to differentiate normal patients from patients with CAD, transplant atherosclerosis, and ACS. They also recently showed that plasma MDA-LDL levels, when measured in the emergency room and combined with troponin I measurements, have very high sensitivity and specificity for detecting ACS. We, too, recently observed in a 7-month prospective study that patients with ACS had up to a 60% increase in autoantibody titers to several model-epitopes of ox-LDL, such as MDA-LDL, copper-oxidized LDL, and 1-palmitoyl-2-(5-oxgualoryl)-3-phosphorylcholine (POVPC), an oxidized phospholipid epitope, as well as an increase in circulating LDL-immune complexes, which peaked over the first month.25 In addition, circulating levels of an oxidation-specific epitope of ox-LDL, defined by EO6,26 a natural murine monoclonal autoantibody that likely binds to an oxidized phospholipid epitope similar to DLH3, was increased by up to 35% in the patients with AMI in the first month after the event.
The above data clearly demonstrate that relatively small amounts of LDL containing different oxidation-specific epitopes can be measured in the bloodstream and may reflect different manifestations of CAD. At present, the etiology of the oxidation-specific epitopes present on plasma LDL is unknown. The source of such ox-LDL could be the direct release of modified LDL from ruptured or permeable plaques, ischemic injury due to damaged cell membranes (either acutely or after reperfusion), or even remote nonatherosclerotic inflammatory sources. Finally, the transfer of such oxidation-specific epitopes from any of these sources to a lipoprotein acceptor, such as LDL, could occur. It is likely that, at least in ACS, all of these mechanisms may contribute.
In more stable patients, it is likely that elevated levels of ox-LDL reflect the turnover of ox-LDL in newly formed or progressing lesions not just in the coronary arteries, but also in the systemic arteries, which have a substantially greater amount of atherosclerotic burden and ox-LDL. For example, noninvasive imaging of hypercholesterolemic rabbit arteries shows that the aorta contains a substantially greater amount of oxidation-specific epitopes than the relatively small coronary arteries.4 It is also well appreciated that in an atherosclerotic milieu, LDL is oxidized more easily. For example, injecting native LDL into rats, or humans with atherosclerosis, results in rapid accumulation of ox-LDL within the artery wall, which can be prevented by pretreatment with probucol or vitamin E, respectively.27 28 Improved methods are needed to evaluate both the rate of oxidation and the presence of ox-LDL within the vessel wall.
Another major question that arises is which epitopes of ox-LDL are better markers of the atherosclerotic process. ox-LDL is a generic term for many different modifications of LDL. For example, MM-LDL primarily represents the oxidation of polyunsaturated fatty acids on phospholipids and cholesterol esters, but the LDL particle is still recognized by the LDL receptor. Fully oxidized LDL represents the depletion of polyunsaturated fatty acids and antioxidants within the LDL core and significant derivatization, cross-linking, and fracturing of the apoB of LDL so that the LDL particle is now recognized by scavenger receptors. Ehara et al2 are likely measuring an oxidized phospholipid epitope of MM-LDL. At this point, it is not clear which epitopes of ox-LDL (eg, oxidized phospholipids, MDA-lysines such as those on MDA-LDL, or others) will be more relevant to certain clinical syndromes. What is needed to answer this question are large prospective trials with clinical end points. A comprehensive panel of different indices of ox-LDL should be measured, including autoantibody measurements to different epitopes of ox-LDL, immune complexes of LDL, and different epitopes of ox-LDL itself to provide a better assessment of the role of ox-LDL in ACS. In addition, the clinical utility of these measurements should be compared with other markers of enhanced lipid peroxidation, such as plasma or urinary isoprostanes, and with other inflammatory markers of plaque activity, such as C-reactive protein or interleukins.29 30 The current data on circulating levels of various markers of ox-LDL do not yet provide enough information for us to determine if they will be of clinical relevance, either in the acute setting or as novel risk factors. Finally, although the studies to date have related indices of ox-LDL to clinical events, levels of ox-LDL may also directly relate to coronary vasomotion, as recently reported by Penny et al.31
Because ox-LDL can be thought of as integral in the final pathway of the many risk factors leading to foam cell formation, it is likely that assays for oxidation-specific epitopes in LDL will have substantial predictive qualities when assessed in larger studies. More studies like that of Ehara et al2 are needed, together with the other measures noted above. If large studies show that such ox-LDL measurements do have predictive value, then their measurement along with the lipid profile and markers of inflammation may improve our ability to provide a more accurate atherosclerotic risk analysis, particularly of acute clinical events.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Dr Witztum serves as an advisor to, and holds stock and options in, Atherogenics, Inc.
References
1. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–924.[Medline] [Order article via Infotrieve]
2.
Ehara S, Ueda M,
Naruko T, et al. Elevated levels of oxidized low density lipoprotein
show a positive correlation with the severity of acute coronary
syndromes. Circulation. 2001;103:1955–1960.
3. Tsimikas S, Witztum JL. The oxidative modification hypothesis of atherosclerosis. In: Keaney JF, ed. Oxidative Stress and Vascular Disease. Boston, Mass: Kluwer Academic Publishers; 2000:49–74.
4. Tsimikas S, Palinski W, Halpern SE, et al. Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol. 1999;6:41–53.[Medline] [Order article via Infotrieve]
5.
Tsimikas S, Shortal
BP, Witztum JL, et al. In vivo uptake of radiolabeled MDA2, an
oxidation-specific monoclonal antibody, provides an accurate measure of
atherosclerotic lesions rich in oxidized LDL and is highly sensitive to
their regression. Arterioscler Thromb Vasc
Biol. 2000;20:689–697.
6.
Berliner JA, Navab
M, Fogelman AM, et al. Atherosclerosis: basic mechanisms oxidation,
inflammation, and genetics.
Circulation. 1995;91:2488–2496.
7.
Aikawa M, Rabkin E,
Okada Y, et al. Lipid lowering by diet reduces matrix metalloproteinase
activity and increases collagen content of rabbit atheroma: a potential
mechanism of lesion stabilization.
Circulation. 1998;97:2433–2444.
8.
Falk E, Shah PK,
Fuster V. Coronary plaque disruption.
Circulation. 1995;92:657–671.
9.
Davies MJ.
Glagovian remodelling, plaque composition, and stenosis generation.
Heart. 2000;84:461–462.
10.
Virmani R,
Kolodgie FD, Burke AP, et al. Lessons from sudden coronary death: a
comprehensive morphological classification scheme for atherosclerotic
lesions. Arterioscler Thromb Vasc
Biol. 2000;20:1262–1275.
11.
Ylä-Herttuala
S, Palinski W, Butler SW, et al. Rabbit and human atherosclerotic
lesions contain IgG that recognizes epitopes of oxidized LDL.
Arterioscler Thromb. 1994;14:32–40.
12. Carpenter KL, Taylor SE, van der Veen C, et al. Lipids and oxidised lipids in human atherosclerotic lesions at different stages of development. Biochim Biophys Acta. 1995;1256:141–150.[Medline] [Order article via Infotrieve]
13. Piotrowski JJ, Shah S, Alexander JJ. Mature human atherosclerotic plaque contains peroxidized phosphatidylcholine as a major lipid peroxide. Life Sci. 1996;58:735–740.[Medline] [Order article via Infotrieve]
14.
Steinbrecher UP,
Witztum JL, Parthasarathy S, et al. Decrease in reactive amino groups
during oxidation or endothelial cell modification of LDL: correlation
with changes in receptor-mediated catabolism.
Arteriosclerosis. 1987;7:135–143.
15.
Van Berkel TJ, De
Rijke YB, Kruijt JK. Different fate in vivo of oxidatively modified low
density lipoprotein and acetylated low density lipoprotein in rats.
Recognition by various scavenger receptors on Kupffer and endothelial
liver cells. J Biol Chem. 1991;266:2282–2289.
16.
Avogaro P, Bon
GB, Cazzolato G. Presence of a modified low density lipoprotein in
humans. Arteriosclerosis. 1988;8:79–87.
17.
Sevanian A, Hwang
J, Hodis H, et al. Contribution of an in vivo oxidized LDL to LDL
oxidation and its association with dense LDL subpopulations.
Arterioscler Thromb Vasc Biol. 1996;16:784–793.
18. Palinski W, Hörkko S, Miller E, et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice: demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996;98:800–814.[Medline] [Order article via Infotrieve]
19. Itabe H, Yamamoto H, Imanaka T, et al. Sensitive detection of oxidatively modified low density lipoprotein using a monoclonal antibody. J Lipid Res. 1996;37:45–53.[Abstract]
20.
Holvoet P,
Vanhaecke J, Janssens S, et al. Oxidized LDL and
malondialdehyde-modified LDL in patients with acute coronary syndromes
and stable coronary artery disease.
Circulation. 1998;98:1487–1494.
21.
Holvoet P,
Stassen JM, Van Cleemput J, et al. Oxidized low density lipoproteins in
patients with transplant-associated coronary artery disease.
Arterioscler Thromb Vasc Biol. 1998;18:100–107.
22. Holvoet P, Collen D, van de Werf F. Malondialdehyde-modified LDL as a marker of acute coronary syndromes. JAMA. 1999;281:1721.
23.
Itabe H, Yamamoto
H, Suzuki M, et al. Oxidized phosphatidylcholines that modify proteins:
analysis by monoclonal antibody against oxidized low density
lipoprotein. J Biol Chem. 1996;271:33208–33217.
24. Shoji T, Nishizawa Y, Fukumoto M, et al. Inverse relationship between circulating oxidized low density lipoprotein (oxLDL) and anti-oxLDL antibody levels in healthy subjects. Atherosclerosis. 2000;148:171–177.[Medline] [Order article via Infotrieve]
25. Tsimikas S, Beyer RW, Patel R, et al. Prospective evaluation of the role of oxidized LDL in acute coronary syndromes treated with percutaneous intervention. Circulation. 2000;102:II-13. Abstract.
26. Hörkkö S, Bird DA, Miller E, et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest. 1999;103:117–128.[Medline] [Order article via Infotrieve]
27.
Calara F,
Dimayuga P, Niemann A, et al. An animal model to study local oxidation
of LDL and its biological effects in the arterial wall.
Arterioscler Thromb Vasc Biol. 1998;18:884–893.
28.
Iuliano L,
Mauriello A, Sbarigia E, et al. Radiolabeled native low-density
lipoprotein injected into patients with carotid stenosis accumulates in
macrophages of atherosclerotic plaque: effect of vitamin E
supplementation. Circulation. 2000;101:1249–1254.
29.
Praticò D,
Barry OP, Lawson JA, et al. IPF2
-I: an index of lipid peroxidation
in humans. Proc Natl Acad Sci
U S A. 1998;95:3449–3454.
30. Lee RT, Libby P. The unstable atheroma. Circulation. 1997;17:1859–1867.
31.
Penny WF,
Ben-Yehuda O, Kuroe K, et al. Improvement of coronary artery
endothelial dysfunction with lipid-lowering therapy: heterogeneity of
segmental response and correlation with plasma-oxidized low density
lipoprotein. J Am Coll Cardiol. 2001;37:766–774.
This article has been cited by other articles:
 |
|
 |
|
  S. Tsimikas, E. S. Brilakis, R. J. Lennon, E. R. Miller, J. L. Witztum, J. P. McConnell, K. S. Kornman, and P. B. Berger Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events J. Lipid Res., February 1, 2007; 48(2): 425 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Mehta Oxidized or Native Low-Density Lipoprotein Cholesterol: Which Is More Important in Atherogenesis? J. Am. Coll. Cardiol., September 5, 2006; 48(5): 980 - 982. [Full Text] [PDF]
|
|
|
|
|
|
J. Rodenburg, M. N. Vissers, A. Wiegman, E. R. Miller, P. M. Ridker, J. L. Witztum, J. J.P. Kastelein, and S. Tsimikas Oxidized Low-Density Lipoprotein in Children With Familial Hypercholesterolemia and Unaffected Siblings: Effect of Pravastatin J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1803 - 1810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Armstrong, D. A. Morrow, and M. S. Sabatine Inflammatory Biomarkers in Acute Coronary Syndromes: Part III: Biomarkers of Oxidative Stress and Angiogenic Growth Factors Circulation, February 28, 2006; 113(8): e289 - e292. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Li and J. L. Mehta Oxidized LDL, a critical factor in atherogenesis Cardiovasc Res, December 1, 2005; 68(3): 353 - 354. [Full Text] [PDF]
|
|
|
|
|
|
K. Hayashida, N. Kume, T. Murase, M. Minami, D. Nakagawa, T. Inada, M. Tanaka, A. Ueda, G. Kominami, H. Kambara, et al. Serum Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels Are Elevated in Acute Coronary Syndrome: A Novel Marker for Early Diagnosis Circulation, August 9, 2005; 112(6): 812 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsimikas, E. S. Brilakis, E. R. Miller, J. P. McConnell, R. J. Lennon, K. S. Kornman, J. L. Witztum, and P. B. Berger Oxidized Phospholipids, Lp(a) Lipoprotein, and Coronary Artery Disease N. Engl. J. Med., July 7, 2005; 353(1): 46 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Januszewski, N. L. Alderson, A. J. Jenkins, S. R. Thorpe, and J. W. Baynes Chemical modification of proteins during peroxidation of phospholipids J. Lipid Res., July 1, 2005; 46(7): 1440 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Fach, L.-A. Garulacan, J. Gao, Q. Xiao, S. M. Storm, Y. P. Dubaquie, S. A. Hefta, and G. J. Opiteck In Vitro Biomarker Discovery for Atherosclerosis by Proteomics Mol. Cell. Proteomics, December 1, 2004; 3(12): 1200 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-L. Liu, K. Ylitalo, R. Salonen, J. T. Salonen, and M.-R. Taskinen Circulating Oxidized Low-Density Lipoprotein and Its Association With Carotid Intima-Media Thickness in Asymptomatic Members of Familial Combined Hyperlipidemia Families Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1492 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS Circulation, October 21, 2003; 108(16): 1912 - 1916. [Full Text] [PDF]
|
|
|
|
|
|
M. M. Engler, M. B. Engler, M. J. Malloy, E. Y. Chiu, M. C. Schloetter, S. M. Paul, M. Stuehlinger, K. Y. Lin, J. P. Cooke, J. D. Morrow, et al. Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial Circulation, September 2, 2003; 108(9): 1059 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, C. Bergmark, R. W. Beyer, R. Patel, J. Pattison, E. Miller, J. Juliano, and J. L. Witztum Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes J. Am. Coll. Cardiol., February 5, 2003; 41(3): 360 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pankhurst, X. L. Wang, D. E. Wilcken, G. Baernthaler, U. Panzenbock, M. Raftery, and R. Stocker Characterization of specifically oxidized apolipoproteins in mildly oxidized high density lipoprotein J. Lipid Res., February 1, 2003; 44(2): 349 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Fang, S. Kinlay, D. Behrendt, H. Hikita, J. L. Witztum, A. P. Selwyn, and P. Ganz Circulating Autoantibodies to Oxidized LDL Correlate With Impaired Coronary Endothelial Function After Cardiac Transplantation Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2044 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Verhamme, R. Quarck, H. Hao, M. Knaapen, S. Dymarkowski, H. Bernar, J. Van Cleemput, S. Janssens, J. Vermylen, G. Gabbiani, et al. Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs Cardiovasc Res, October 1, 2002; 56(1): 135 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hulthe and B. Fagerberg Circulating Oxidized LDL Is Associated With Subclinical Atherosclerosis Development and Inflammatory Cytokines (AIR Study) Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1162 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Subbanagounder, J. W. Wong, H. Lee, K. F. Faull, E. Miller, J. L. Witztum, and J. A. Berliner Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis. FORMATION OF THESE OXIDIZED PHOSPHOLIPIDS IN RESPONSE TO INTERLEUKIN-1beta J. Biol. Chem., February 22, 2002; 277(9): 7271 - 7281. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||