© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Interleukin-6 Exacerbates Early Atherosclerosis in Mice
From the Departments of Pathology (S.A.H., P.S., N.H., R.T.), Medicine (D.C.), and Biochemistry (R.T.), University of Vermont, Burlington, VT 05405.
Correspondence to Sally Ann Huber, PhD, Department of Pathology, University of Vermont, 55A South Park Drive, Colchester, VT 05446. E-mail shuber{at}salus.uvm.edu
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Abstract |
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Abstract—Acute-phase proteins, which respond to systemic proinflammatory cytokines such as interleuken-6, are elevated in cardiovascular disease and are predictive markers of future ischemic events, even over decades. This suggests a role for proinflammatory cytokines and/or acute phase proteins in early lesion development. To explore this issue, we fed C57Bl/6 and nonobese diabetic male mice high-fat (20% total fat, 1.5% cholesterol) diets and ApoE-deficient male mice both high-fat and normal chow diets for 6 to 21 weeks, injecting them weekly with either 5000 U recombinant interleukin-6 (rIL-6) or saline buffer. Blood was collected when animals were euthanized and assayed for cytokines, acute-phase proteins, and cholesterol. Across all mice, IL-6 injection resulted in significant increases in proinflammatory cytokines (IL-6, 4.6-fold; IL-1ß, 1.6-fold; and tissue necrosis factor-
,
1.7-fold) and fibrinogen (1.2-fold) and with decreased concentrations
of albumin (0.9-fold) in plasma. Total cholesterol
levels were unchanged between rIL-6–treated and nontreated groups.
Serial sections through the aortic sinus were stained with oil red O to
detect fatty streaks, and area of the lesions was determined by image
analysis. Although no fatty streaks were detected in the
nonobese diabetic mice with or without rIL-6 treatment, rIL-6 treatment
increased lesion size in C57Bl/6 and ApoE-deficient mice 1.9- to
5.1-fold over lesions in saline-treated animals. These results suggest
that under the appropriate circumstances changes in circulating
proinflammatory cytokines and acute-phase proteins may be more
than just markers of atherosclerosis but actual
participants in early lesion development.
Key Words: inflammation • atherosclerosis • interleukin-6
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Introduction |
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Interleukin-6 (IL-6) belongs to a family of 20kDa polypeptide cytokines having a four-long-chain
–helix-bundle structure.1 2 3 This family includes
IL-11, leukemia inhibitory factor, oncostatin M, ciliary
neurotropic factor, and cardiotropin-1. The IL-6–type
cytokines use the same receptor gp130 subunit for signal
transduction resulting in activation of the Janus kinase pathway. Thus
these cytokines may induce similar
physiological responses and participate in various
aspects of cell proliferation and differentiation.
Macrophage/monocytes, T cells, endothelial
cells, fibroblasts, smooth muscle cells, osteoblasts, and chondrocytes
are primarily identified with IL-6 production, usually as a
result of interleuken-1ß (IL-1ß), tissue necrosis factor-
(TNF), transforming growth factor-ß, or
lipopolysaccharide stimulation. The major biological effects of
IL-6 are proliferation and differentiation of B and T
lymphocytes4 and regulation of the acute-phase
response.5
Cardiovascular disease (CVD) likely represents,
at least in part, a chronic low-level inflammatory process
characterized by increased circulating levels of proinflammatory
cytokines (IL-6, TNF, and IL-1ß), soluble adhesion
molecules (intracellular adhesion molecule-1 and P-selectin), and
cytokine-responsive acute phase proteins including C-reactive
protein (CRP), plasminogen-activator
inhibitor-1 (PAI-1), and fibrinogen.6
Increased levels of CRP7 8 and IL-69 in
patients with unstable angina are associated with poor prognostic
outcome. More recently, several studies indicate that CRP can be an
independent predictive risk factor for CVD in apparently healthy
middle-aged men over long-time periods, even decades,10 11
suggesting a possible association with early lesion development.
A major question is whether increased levels of risk markers such as proinflammatory cytokines, CRP, and/or fibrinogen12 simply result from the developing underlying disease or whether these factors also participate directly in the disease process. To investigate whether IL-6 directly promotes fatty lesion development, we placed atherosclerosis-prone (C57Bl/6, ApoE-deficient [ApoE-]) and atherosclerosis-resistant (nonobese diabetic [NOD]) mice on high-fat, high-cholesterol diets and gave the animals weekly injections of recombinant mouse IL-6. The results show that exogenously administered IL-6 significantly enhanced fatty lesion development in the atherosclerosis-prone, but not in the atherosclerosis-resistant, animals, suggesting that inflammatory factors likely play an active role in the disease process.
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Methods |
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Mice
Male C57Bl/6, NOD, and ApoE- mice were purchased from Jackson Laboratories (Bar Harbor, ME) at 3 weeks of age and fed ad libum either a low-fat diet (Teklad # 7012: 5.67% fat, 0% cholesterol) or a high-fat diet (Teklad # 96354: 20% fat, 1.5% cholesterol, 0.5% sodium cholate) for either 6 or 21 weeks.
Plasma Analysis
Blood was collected by cardiac puncture when animals were
euthanized (one week after the final injection), and
ethylenediamine-tetraacetic acid plasma was prepared.
Cholesterol, glucose, and albumin were determined
using the Vitros CHOL and Vitros ALB slide methods (Johnson & Johnson
Clinical Diagnostics, Inc). Fibrinogen was determined by a
clot-rate assay, modified from the original Clauss assay13
for use with ethylenediamine-tetraacetic acid
plasma.14
Cytokine and ELISA
Recombinant mouse IL-6 was purchased from Genzyme
(Cambridge, Mass). Plasma concentrations of TNF, IL-1, and IL-6 were
determined by capture ELISA using commercial kits from Pharmingen and
performed according to manufacturer's directions.
Histology
The heart and ascending aorta, including the aortic arch, were
removed and evaluated for atherosclerotic lesions according to the
method of Plump et al15 using oil Red O stained serial
sections. Hearts were fixed in 10% buffered formalin, embedded
sequentially in 5%, 10%, and 25% gelatin, grossly cut through the
ventricles parallel to the atria, and frozen in O.C.T (Miles
Laboratories). Every other 10-micron section was placed on gelatin
coated slides, stained with 0.24% oil Red O, and counterstained with
2.4% hematoxylin and 0.25% light green. Stained sections were
evaluated by image analysis in transmitted light mode with an
Olympus BX50 compound light microscope (4x objective lens;
numerical aperture, 0.13). True-color digital images (640 by 480
pixels) were captured with a Sony DXC-960 MD/LLP video camera connected
via an RS170 cable to a video frame grabber on a Sun SPARCstation 5.
Image processing and analysis were accomplished with IMIX
software (Princeton Gamma Tech, Inc). Final lesion size was
calculated as the mean lesion area in 4 sections, 80 µm
apart.
Experimental Design and Statistics
As shown in the Table
, we defined 4 experimental pairs in this
study: (I) C57Bl/6, high-fat diet, ±IL-6; (II) NOD, high-fat diet,
±IL-6; (III) ApoE-, high-fat diet, ±IL-6; and
(IV) ApoE-, low-fat diet, ±IL-6. Starting group
sizes for mice ranged from 5 to 7. The smallest group size examined at
the end of an experiment was 3, due to the death of 2 mice. Levels of
blood components were analyzed 2 ways. First, we compared raw
values between IL-6–treated and nontreated mice for each experimental
pair. Second, we combined data from all animals across the 4
experiments by normalizing each animal's value for a given assay to
the mean for the non-IL-6–treated animals in their experimental pair.
Data were evaluated by Student's t test.
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Results |
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Male atherosclerosis-prone (C57Bl/6, ApoE-) and atherosclerosis-resistant (NOD) mice were maintained on high-fat or normal diet from 3 weeks of age until euthanization. ApoE- mice on high-fat diet (Experimental pair III) were euthanized at 9 weeks of age because fatty streak development in these mice is known to progress rapidly.16 In contrast, lesion progression is slower in ApoE- mice on low-fat diet and in C57Bl/6 wild-type mice. Thus the animals in Experimental pairs I, II, and IV were euthanized at 24 weeks of age to allow adequate lesion development. Plasma from individual animals was evaluated for cholesterol, glucose, fibrinogen, albumin, IL-6, IL-1, and TNF
concentrations, and hearts were sectioned through the
aortic sinus and lesion size by the method of Plump et
al.15 Results are shown in the Table
by
experimental pair. The most significant observation from this study is
that rIL-6 treatment of atherosclerosis-prone mice
(C57Bl/6 and ApoE-) significantly increased
lesion size over noncytokine-treated animals. NOD mice failed
to develop fatty lesions with or without rIL-6. Lesions in all mice
appeared similar by microscopy, although different in extent. No significant differences were observed between IL-6–treated and nontreated mice for total body weight or plasma cholesterol levels. Two of seven NOD mice developed hyperglycemia in both cytokine-treated and nontreated groups; however, no significant difference in glucose levels was observed between groups. Mean fibrinogen concentrations tended to be elevated and albumin concentrations tended to be lower in C57Bl/6 and ApoE- mice given rIL-6 compared with identical mice without cytokine, whereas cholesterol levels were similar between IL-6–treated and nontreated mice.
Proinflammatory cytokine concentrations were
elevated in the plasma of IL-6–treated mice. This was most dramatic
for IL-6 levels, especially in ApoE- mice on
high-fat diets where plasma IL-6 concentrations increased from 0.14
ng/mL in noncytokine-treated animals to 1.10 ng/mL in
IL-6–treated mice. The other 2 proinflammatory cytokines,
TNF and IL-1ß, were also increased in the plasma of IL-6–treated
animals.
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Discussion |
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This study shows that IL-6, a proinflammatory cytokine, enhanced fatty lesion development in atherosclerosis-prone mice. The effect was most pronounced in strains of animals that normally develop modest lesions. IL-6 treatment of C57Bl/6 mice resulted in a 5.1-fold increase in fatty streak size (from 410 to 2090 µm2), whereas treatment of ApoE- mice on low- or high-fat diets resulted in 2.4- and 1.9-fold increases. ApoE- mice on either diet developed substantially greater lesions than C57Bl/6 parental mice, most likely because total cholesterol levels were considerably higher. Because the ApoE- mice develop such rapid and extensive lesions, the effects of exogenously administered IL-6 may be less obvious than in C57Bl/6 animals, which have modest cholesterol levels and develop smaller lesions at a much lower rate.
Fatty streaks result from the accumulation of fat-laden
macrophages (foam cells) in the subendothelial
spaces. Monocytes, the progenitors of early foam cells, are involved in
lesion development and must adhere to and migrate through the
endothelium at the site of fatty
streak/atheromatous lesion
development.17 18 19 Cell adhesion molecules on
endothelial cells, such as ICAM-1, VCAM-1, E-selectin,
and P-selectin, promote leukocyte migration.18 These
cell-adhesion molecules interact with specific ligands on leukocytes:
ICAM-1 with LFA-1, Mac-1; VCAM-1 with VLA-4.19 Expression
of these adhesion molecules can be greatly enhanced by specific
cytokines (IL-1ß, TNF, and IFN
). These
cytokines also activate macrophage-monocytes,
which increases their stickiness, mobility, phagocytosis, and enzyme
levels. All of these effects would be expected to increase lipid
uptake, LDL oxidation, and cell migration into the intima. Furthermore,
these proinflammatory cytokines promote proliferation of
various cell types, including smooth muscle cells, and increase
extracellular matrix production.20 21
Although endothelial cells are likely targets of proinflammatory mediators, other cells are targets, and also producers, of these cytokines. Substantial numbers of cells expressing T-cell markers are found in fatty streaks and advanced lesions in humans17 22 23 and in fatty streaks in mice.24 Although controversial, several investigators have found that depleting mice of CD4+ T cells significantly reduces the size of fatty lesions compared with immunocompetent control animals.24 25 IL-6 is a potent lymphocyte growth factor, which could extend clonal expansion of pathogenic CD4+ lymphocytes in the fatty lesion. IL-6 also regulates T cell differentiation and cytokine production, which may select for immune responses conducive to lesion formation.
In addition, the effects of IL-6 on hepatic acute phase reactants can also impact atherogenesis. IL-6–treated animals showed significantly increased fibrinogen and decreased albumin when normalized to nontreated controls. Increasing fibrinogen concentrations can augment blood clotting,12 whereas decreasing albumin may increase platelet reactivity,26 27 both of which could contribute to disease progression in humans. Other potentially important inflammation mediators, which we did not examine, include the fibrinolytic regulators tissue plasminogen activator, PAI-1, and CRP, which has been shown to increase tissue factor expression on monocytes.28
One of the intriguing observations in the present study is that IL-6 did not cause fatty streak induction in atherosclerosis-resistant NOD mice. Plasma cholesterol levels and proinflammatory cytokine concentrations were as high or higher in these animals than in the susceptible C57Bl/6 animals. The results indicate that although a high-cholesterol diet or circulating proinflammatory cytokines such as IL-6 can promote fatty streak formation, these risk factors cannot overcome inherent genetic traits causing disease resistance. The identity of these genetic resistance trait(s) are unknown.
The relationship between fatty streaks in mice and atheromatous plaques in humans is controversial. To date, the complex advanced atherosclerotic lesions observed in humans has not been duplicated in the mouse, raising the issue of relevance of the mouse model system. Fatty streaks may occur in areas of the aorta not normally associated with atheromatous plaques and in children living in geographical regions in which atheromatous plaques are infrequent. Undoubtedly, not all fatty streaks progress to atheromas.29 30 31 32 In contrast, fatty streaks in coronary arteries occur in anatomical sites prone to atheromatous plaque development and appear to correlate to and precede mature lesions in humans.33 34 Evidence from experimental models further links fatty streaks to atherosclerotic plaques. Faggiotto and Ross35 studied nonhuman primates and demonstrated that advanced lesions developed in anatomical sites first associated with fatty streaks. Thus, although undoubtedly all fatty streaks do not progress to atheromas, some do. T lymphocytes and foam cells are found in fatty streaks of both humans and mice, and extensive studies over the last 40 years indicate that most immunological processes are either identical or quite similar between these 2 species. Thus, although the mouse may not be applicable to all studies in atherogenesis, it may provide important insights into the role of immune and inflammatory mediators in fatty streak development.
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Acknowledgments |
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This work was supported by NHLBI awards RO1-HL-46696 (R.T.), RO1-HL-58583 (S.A.H.), and T32-HL-07594 (P.S.); and the Department of Pathology, University of Vermont College of Medicine. We thank Drs Jonathan Smith and Jan Breslow for helpful discussions and training regarding the measurement of lesion size. We also thank Dr Mercedes Rincon for her valuable discussions on IL-6.
Received December 7, 1998; accepted February 22, 1999.
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W. Koenig and N. Khuseyinova Biomarkers of Atherosclerotic Plaque Instability and Rupture Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]
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 R. Mehra, A. Storfer-Isser, H. L. Kirchner, N. Johnson, N. Jenny, R. P. Tracy, and S. Redline Soluble interleukin 6 receptor: a novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med, September 18, 2006; 166(16): 1725 - 1731. [Abstract] [Full Text] [PDF]
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N. Takeda, I. Manabe, T. Shindo, H. Iwata, S. Iimuro, H. Kagechika, K. Shudo, and R. Nagai Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6 Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1177 - 1183. [Abstract] [Full Text] [PDF]
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 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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V. A. Korshunov, T. A. Nikonenko, V. A. Tkachuk, A. Brooks, and B. C. Berk Interleukin-18 and Macrophage Migration Inhibitory Factor Are Associated With Increased Carotid Intima-Media Thickening Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 295 - 300. [Abstract] [Full Text] [PDF]
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J. George, A. Afek, A. Abashidze, H. Shmilovich, V. Deutsch, J. Kopolovich, H. Miller, and G. Keren Transfer of Endothelial Progenitor and Bone Marrow Cells Influences Atherosclerotic Plaque Size and Composition in Apolipoprotein E Knockout Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2636 - 2641. [Abstract] [Full Text] [PDF]
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 A. M Carter Inflammation, thrombosis and acute coronary syndromes Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 113 - 121. [Abstract] [PDF]
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 B. Nashed, B. Yeganeh, K. T. HayGlass, and M. H. Moghadasian Antiatherogenic Effects of Dietary Plant Sterols Are Associated with Inhibition of Proinflammatory Cytokine Production in Apo E-KO Mice J. Nutr., October 1, 2005; 135(10): 2438 - 2444. [Abstract] [Full Text] [PDF]
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 J. Y. King, R. Ferrara, R. Tabibiazar, J. M. Spin, M. M. Chen, A. Kuchinsky, A. Vailaya, R. Kincaid, A. Tsalenko, D. X.-F. Deng, et al. Pathway analysis of coronary atherosclerosis Physiol Genomics, September 21, 2005; 23(1): 103 - 118. [Abstract] [Full Text] [PDF]
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J. Tian, K. Ishibashi, K. Ishibashi, K. Reiser, R. Grebe, S. Biswal, P. Gehlbach, and J. T. Handa Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response PNAS, August 16, 2005; 102(33): 11846 - 11851. [Abstract] [Full Text] [PDF]
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 Y. Li, R. F. Schwabe, T. DeVries-Seimon, P. M. Yao, M.-C. Gerbod-Giannone, A. R. Tall, R. J. Davis, R. Flavell, D. A. Brenner, and I. Tabas Free Cholesterol-loaded Macrophages Are an Abundant Source of Tumor Necrosis Factor-{alpha} and Interleukin-6: MODEL OF NF-{kappa}B- AND MAP KINASE-DEPENDENT INFLAMMATION IN ADVANCED ATHEROSCLEROSIS J. Biol. Chem., June 10, 2005; 280(23): 21763 - 21772. [Abstract] [Full Text] [PDF]
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G. M. Hirschfield, J. R. Gallimore, M. C. Kahan, W. L. Hutchinson, C. A. Sabin, G. M. Benson, A. P. Dhillon, G. A. Tennent, and M. B. Pepys Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice PNAS, June 7, 2005; 102(23): 8309 - 8314. [Abstract] [Full Text] [PDF]
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M. P.J. de Winther, E. Kanters, G. Kraal, and M. H. Hofker Nuclear Factor {kappa}B Signaling in Atherogenesis Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 904 - 914. [Abstract] [Full Text] [PDF]
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S. B. Kritchevsky, M. Cesari, and M. Pahor Inflammatory markers and cardiovascular health in older adults Cardiovasc Res, May 1, 2005; 66(2): 265 - 275. [Abstract] [Full Text] [PDF]
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M. Weger, I. Steinbrugger, A. Haas, W. Marz, Y. El-Shabrawi, W. Weger, O. Schmut, and W. Renner Role of the Interleukin-6 -174 G>C Gene Polymorphism in Retinal Artery Occlusion Stroke, February 1, 2005; 36(2): 249 - 252. [Abstract] [Full Text] [PDF]
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 S. Devaraj, S. K. Venugopal, U. Singh, and I. Jialal Hyperglycemia Induces Monocytic Release of Interleukin-6 via Induction of Protein Kinase C-{alpha} and -{beta} Diabetes, January 1, 2005; 54(1): 85 - 91. [Abstract] [Full Text] [PDF]
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 B. Schieffer, T. Selle, A. Hilfiker, D. Hilfiker-Kleiner, K. Grote, U. J.F. Tietge, C. Trautwein, M. Luchtefeld, C. Schmittkamp, S. Heeneman, et al. Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis Circulation, November 30, 2004; 110(22): 3493 - 3500. [Abstract] [Full Text] [PDF]
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 K. M. Prestwood, C. Unson, M. Kulldorff, and M. Cushman The Effect of Different Doses of Micronized 17{beta}-Estradiol on C-Reactive Protein, Interleukin-6, and Lipids in Older Women J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2004; 59(8): M827 - M832. [Abstract] [Full Text] [PDF]
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 S. Upadhya, S. Mooteri, N. Peckham, and R. G. Pai Atherogenic Effect of Interleukin-2 and Antiatherogenic Effect of Interleukin-2 Antibody in Apo-E-Deficient Mice Angiology, May 1, 2004; 55(3): 289 - 294. [Abstract] [PDF]
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S. Wassmann, M. Stumpf, K. Strehlow, A. Schmid, B. Schieffer, M. Bohm, and G. Nickenig Interleukin-6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor Circ. Res., March 5, 2004; 94(4): 534 - 541. [Abstract] [Full Text] [PDF]
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E. Tupin, A. Nicoletti, R. Elhage, M. Rudling, H.-G. Ljunggren, G. K. Hansson, and G. P. Berne CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis J. Exp. Med., February 2, 2004; 199(3): 417 - 422. [Abstract] [Full Text] [PDF]
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
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 R. P. Tracy Thrombin, Inflammation, and Cardiovascular Disease: An Epidemiologic Perspective Chest, September 1, 2003; 124(3_suppl): 49S - 57S. [Abstract] [Full Text] [PDF]
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 C. M.L. Chapman, J. P. Beilby, S. E. Humphries, L. J. Palmer, P. L. Thompson, and J. Hung Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population Eur. Heart J., August 2, 2003; 24(16): 1494 - 1499. [Abstract] [Full Text] [PDF]
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F. M. Rauscher, P. J. Goldschmidt-Clermont, B. H. Davis, T. Wang, D. Gregg, P. Ramaswami, A. M. Pippen, B. H. Annex, C. Dong, and D. A. Taylor Aging, Progenitor Cell Exhaustion, and Atherosclerosis Circulation, July 29, 2003; 108(4): 457 - 463. [Abstract] [Full Text] [PDF]
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 P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1927 - 1939. [Full Text] [PDF]
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M. Huang, X. Pang, K. Karalis, and T. C. Theoharides Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice Cardiovasc Res, July 1, 2003; 59(1): 241 - 249. [Abstract] [Full Text] [PDF]
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 R. Pecoits-Filho, B. Lindholm, J. Axelsson, and P. Stenvinkel Update on interleukin-6 and its role in chronic renal failure Nephrol. Dial. Transplant., June 1, 2003; 18(6): 1042 - 1045. [Full Text] [PDF]
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G. G. Deng, B. Martin-McNulty, D. A. Sukovich, A. Freay, M. Halks-Miller, T. Thinnes, D. J. Loskutoff, P. Carmeliet, W. P. Dole, and Y.-X. Wang Urokinase-Type Plasminogen Activator Plays a Critical Role in Angiotensin II-Induced Abdominal Aortic Aneurysm Circ. Res., March 21, 2003; 92(5): 510 - 517. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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P. Jerrard-Dunne, M. Sitzer, P. Risley, D. A. Steckel, A. Buehler, S. von Kegler, and H. S. Markus Interleukin-6 Promoter Polymorphism Modulates the Effects of Heavy Alcohol Consumption on Early Carotid Artery Atherosclerosis: The Carotid Atherosclerosis Progression Study (CAPS) Stroke, February 1, 2003; 34(2): 402 - 407. [Abstract] [Full Text] [PDF]
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 U. N. Das Is Metabolic Syndrome X an Inflammatory Condition? Experimental Biology and Medicine, December 1, 2002; 227(11): 989 - 997. [Abstract] [Full Text]
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A. Vink, A. H. Schoneveld, J. J. van der Meer, B. J. van Middelaar, J. P.G. Sluijter, M. B. Smeets, P. H.A. Quax, S. K. Lim, C. Borst, G. Pasterkamp, et al. In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions Circulation, October 8, 2002; 106(15): 1985 - 1990. [Abstract] [Full Text] [PDF]
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R. Pecoits-Filho, P. Barany, B. Lindholm, O. Heimburger, and P. Stenvinkel Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment Nephrol. Dial. Transplant., September 1, 2002; 17(9): 1684 - 1688. [Abstract] [Full Text] [PDF]
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R. P. Choudhury, V. Fuster, J. J. Badimon, E. A. Fisher, and Z. A. Fayad MRI and Characterization of Atherosclerotic Plaque: Emerging Applications and Molecular Imaging Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1065 - 1074. [Abstract] [Full Text] [PDF]
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I. M. van der Meer, M. P.M. de Maat, M. L. Bots, M. M.B. Breteler, J. Meijer, A. J. Kiliaan, A. Hofman, and J. C.M. Witteman Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis: The Rotterdam Study Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 838 - 842. [Abstract] [Full Text] [PDF]
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 S. N. Han, L. S. Leka, A. H. Lichtenstein, L. M. Ausman, E. J. Schaefer, and S. N. Meydani Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory responses of adults with moderate hypercholesterolemia J. Lipid Res., March 1, 2002; 43(3): 445 - 452. [Abstract] [Full Text] [PDF]
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 D J Brull, J Sanders, A Rumley, G D Lowe, S E Humphries, and H E Montgomery Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release Heart, March 1, 2002; 87(3): 252 - 255. [Abstract] [Full Text] [PDF]
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 J. Pfeilschifter, R. Koditz, M. Pfohl, and H. Schatz Changes in Proinflammatory Cytokine Activity after Menopause Endocr. Rev., February 1, 2002; 23(1): 90 - 119. [Abstract] [Full Text] [PDF]
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Y.-X. Wang, B. Martin-McNulty, A. D. Freay, D. A. Sukovich, M. Halks-Miller, W.-W. Li, R. Vergona, M. E. Sullivan, J. Morser, W. P. Dole, et al. Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice Am. J. Pathol., October 1, 2001; 159(4): 1455 - 1464. [Abstract] [Full Text]
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D.J. Brull, H.E. Montgomery, J. Sanders, S. Dhamrait, L. Luong, A. Rumley, G.D.O. Lowe, and S.E. Humphries Interleukin-6 Gene -174G>C and -572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1458 - 1463. [Abstract] [Full Text] [PDF]
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S. Keidar, R. Heinrich, M. Kaplan, T. Hayek, and M. Aviram Angiotensin II Administration to Atherosclerotic Mice Increases Macrophage Uptake of Oxidized LDL: A Possible Role for Interleukin-6 Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1464 - 1469. [Abstract] [Full Text] [PDF]
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H.-A. Lehr, T. A. Sagban, C. Ihling, U. Zahringer, K.-D. Hungerer, M. Blumrich, K. Reifenberg, and S. Bhakdi Immunopathogenesis of Atherosclerosis: Endotoxin Accelerates Atherosclerosis in Rabbits on Hypercholesterolemic Diet Circulation, August 21, 2001; 104(8): 914 - 920. [Abstract] [Full Text] [PDF]
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R. P. Tracy Is Visceral Adiposity the "Enemy Within"? Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 881 - 883. [Full Text] [PDF]
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S. A. Huber, P. Sakkinen, C. David, M. K. Newell, and R. P. Tracy T Helper-Cell Phenotype Regulates Atherosclerosis in Mice Under Conditions of Mild Hypercholesterolemia Circulation, May 29, 2001; 103(21): 2610 - 2616. [Abstract] [Full Text] [PDF]
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G.C. Viberti and S.M. Thomas Searching for new coronary heart disease risk factors Eur. Heart J., December 1, 2000; 21(23): 1905 - 1906. [PDF]
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P. K. Shah Circulating Markers of Inflammation for Vascular Risk Prediction : Are they Ready for Prime Time Circulation, April 18, 2000; 101(15): 1758 - 1759. [Full Text] [PDF]
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L. H. Kuller and R. P. Tracy The Role of Inflammation in Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 901 - 901. [Full Text] [PDF]
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H. Peilot, B. Rosengren, G. Bondjers, and E. Hurt-Camejo Interferon-gamma Induces Secretory Group IIA Phospholipase A2 in Human Arterial Smooth Muscle Cells. INVOLVEMENT OF CELL DIFFERENTIATION, STAT-3 ACTIVATION, AND MODULATION BY OTHER CYTOKINES J. Biol. Chem., July 21, 2000; 275(30): 22895 - 22904. [Abstract] [Full Text] [PDF]
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B. J. Van Lenten, A. C. Wagner, M. Navab, and A. M. Fogelman Oxidized Phospholipids Induce Changes in Hepatic Paraoxonase and ApoJ but Not Monocyte Chemoattractant Protein-1 via Interleukin-6 J. Biol. Chem., January 12, 2001; 276(3): 1923 - 1929. [Abstract] [Full Text] [PDF]
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