Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1257-1266
Published online before print May 9, 2002, doi: 10.1161/01.ATV.0000021412.56621.A2
Published online before print May 9, 2002, doi: 10.1161/01.ATV.0000021412.56621.A2
© 2002 American Heart Association, Inc.
ATVB In Focus |
Vascular Inflammation and the Renin-Angiotensin System
From the Departments of Medicine (A.R.B., A.R., M.S.E.) and Human Biological Chemistry and Genetics (A.R.B.) and the Sealy Center for Molecular Sciences (A.R.B.), The University of Texas Medical Branch, Galveston.
Correspondence to Allan R. Brasier, Division of Endocrinology, MRB 8.138, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1060. E-mail arbrasie{at}utmb.edu
Abstract
It is now well established that vascular inflammation is an independent risk factor for the development of atherosclerosis. In otherwise healthy patients, chronic elevations of circulating interleukin-6 or its biomarkers are predictors for increased risk in the development and progression of ischemic heart disease. Although multifactorial in etiology, vascular inflammation produces atherosclerosis by the continuous recruitment of circulating monocytes into the vessel wall and by contributing to an oxidant-rich inflammatory milieu that induces phenotypic changes in resident (noninflammatory) cells. In addition, the renin-angiotensin system (RAS) has important modulatory activities in the atherogenic process. Recent work has shown that angiotensin II (Ang II) has significant proinflammatory actions in the vascular wall, inducing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules. These latter effects on gene expression are mediated, at least in part, through the cytoplasmic nuclear factor-
B transcription factor. Through these actions, Ang II augments vascular inflammation, induces endothelial dysfunction, and, in so doing, enhances the atherogenic process. Our recent studies have defined a molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone. Ang II produced locally by the inflamed vessel induces the synthesis and secretion of interleukin-6, a cytokine that induces synthesis of angiotensinogen in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. Enhanced angiotensinogen production, in turn, supplies more substrate to the activated vascular RAS, where locally produced Ang II synergizes with oxidized lipid to perpetuate atherosclerotic vascular inflammation. These observations suggest that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation. Moreover, antagonizing the vascular nuclear factor-B and/or hepatic JAK/STAT pathways may modulate the atherosclerotic process.
Key Words: atherosclerosis • interleukin-6 • angiotensin II • angiotensinogen • hepatic acute-phase response
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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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T. M. Doherty, L. A. Fitzpatrick, A. Shaheen, T. B. Rajavashisth, and R. C. Detrano Genetic Determinants of Arterial Calcification Associated With Atherosclerosis Mayo Clin. Proc., February 1, 2004; 79(2): 197 - 210. [Abstract] [PDF]
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K. Tokuda, H. Kai, F. Kuwahara, H. Yasukawa, N. Tahara, H. Kudo, K. Takemiya, M. Koga, T. Yamamoto, and T. Imaizumi Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis Hypertension, February 1, 2004; 43(2): 499 - 503. [Abstract] [Full Text] [PDF]
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 H. D. Sesso, J. E. Buring, N. Rifai, G. J. Blake, J. M. Gaziano, and P. M. Ridker C-Reactive Protein and the Risk of Developing Hypertension JAMA, December 10, 2003; 290(22): 2945 - 2951. [Abstract] [Full Text] [PDF]
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 M. Di Napoli and F. Papa Angiotensin-Converting Enzyme Inhibitor Use Is Associated With Reduced Plasma Concentration of C-Reactive Protein in Patients With First-Ever Ischemic Stroke Stroke, December 1, 2003; 34(12): 2922 - 2929. [Abstract] [Full Text] [PDF]
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T. Minamino, T. Yoshida, K. Tateno, H. Miyauchi, Y. Zou, H. Toko, and I. Komuro Ras Induces Vascular Smooth Muscle Cell Senescence and Inflammation in Human Atherosclerosis Circulation, November 4, 2003; 108(18): 2264 - 2269. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz Multiple actions of angiotensin II in hypertension: benefits of AT1 receptor blockade J. Am. Coll. Cardiol., September 3, 2003; 42(5): 911 - 913. [Full Text] [PDF]
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K. Saraff, F. Babamusta, L. A. Cassis, and A. Daugherty Aortic Dissection Precedes Formation of Aneurysms and Atherosclerosis in Angiotensin II-Infused, Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1621 - 1626. [Abstract] [Full Text] [PDF]
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 R. Bataller, E. Gabele, R. Schoonhoven, T. Morris, M. Lehnert, L. Yang, D. A. Brenner, and R. A. Rippe Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver Am J Physiol Gastrointest Liver Physiol, August 8, 2003; 285(3): G642 - G651. [Abstract] [Full Text] [PDF]
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A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]
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P. Dandona, A. Aljada, A. Chaudhuri, and A. Bandyopadhyay The Potential Influence of Inflammation and Insulin Resistance on the Pathogenesis and Treatment of Atherosclerosis-Related Complications in Type 2 Diabetes J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2422 - 2429. [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz Inflammation and Vascular Hypertrophy Induced by Angiotensin II: Role of NADPH Oxidase-Derived Reactive Oxygen Species Independently of Blood Pressure Elevation? Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 707 - 709. [Full Text] [PDF]
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M. Di Napoli and F. Papa C-Reactive Protein and Blood Pressure in the Acute Phase After an Ischemic Stroke Stroke, April 1, 2003; 34(4): 839 - 839. [Full Text] [PDF]
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J. D. Morrow Is Oxidant Stress a Connection Between Obesity and Atherosclerosis? Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 368 - 370. [Full Text] [PDF]
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 R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [Abstract] [PDF]
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M. S. Runge Extracellular Mediators in Atherosclerosis and Thrombosis Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1256 - 1256. [Full Text] [PDF]
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