[Frontiers in Bioscience 9, 359-369, January 1, 2004]
ANGIOTENSIN II, PPAR-GAMMA AND ATHEROSCLEROSIS
Ulrich Kintscher 1, Christopher J. Lyon 2 and Ronald E. Law 2
1Institute of Pharmacology and Toxicology, Charité Hospital, Humboldt-University Berlin, D-10117 Berlin, Germany and 2 University of California, Los Angeles, School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los Angeles, CA 90095, USA
TABLE OF CONTENTS
Atherosclerosis is a complex, chronic disease state that usually arises from the converging action of several pathogenic processes, including hypertension, hyperlidemia, obesity and insulin resistance. Significantly, due to the increasing incidence of type 2 diabetes worldwide, several aspects of the renin-angiotensin system, including the capacity for angiotensin II synthesis and binding are increased in human and animal models of type II diabetes, and potentiate vascular lesion formation. Angiotensin II, an important vasoactive peptide of the renin-angiotensin system, profoundly accelerates atherosclerosis in animal models of diabetes. Conversely, in both human and animal studies, inhibition of angiotensin II synthesis or activity has been shown to significantly reduce atherosclerosis and cardiovascular mortality. Cardiovascular protection is independent of blood pressure and baseline activity of the renin-angiotensin system, suggesting an important and direct role for the vascular renin-angiotensin system in atherosclerotic progression. Angiotensin II appears to accelerate atherosclerosis through activation of several distinct signal transduction pathways, and via these mechanisms can function as a vascular growth and migration factor, a pro-inflammatory cytokine and an oxidative stress agent. Thiazolidinediones, a class of oral insulin-sensitizing agents in broad clinical use for the treatment of type 2 diabetes, have been shown to ameliorate cardiovascular disease in animal trials and clinical studies. Thiazolidinediones also appear to regulate angiotensin II signaling at multiple levels, significantly reducing the expression of the angiotensin II type 1 receptor and repressing signal transduction through this receptor to suppress vascular remodeling, lesion formation, and oxidative stress.