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(Circulation. 2002;105:530.)
© 2002 American Heart Association, Inc.

Current Perspectives

The AT₁-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis

Part II: AT₁ Receptor Regulation

Georg Nickenig, MD; David G. Harrison, MD

From Klinik und Poliklinik Innere Medizin III (G.N.), Universität des Saarlandes, Homburg/Saar, Germany; and the Department of Medicine (D.G.H.), Division of Cardiology, Medical School of Emory University, Atlanta, Ga.

Correspondence to Dr Georg Nickenig, Klinik und Poliklinik Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany. E-mail nickenig@med-in.uni-sb.de

Key Words: atherosclerosis • angiotensin • genes • vasculature • endothelium

	Introduction

 
Despite intense investigation in the last decade, many questions concerning the etiology of atherosclerosis remain unanswered. Hypercholesterolemia and hypertension are clearly risk factors for the development of vascular lesions, although the precise molecular steps between elevated lipid or blood pressure levels and the development of atherosclerotic lesions are not completely defined.^1,2 Hypertension is frequently associated with additional risk factors such as hypercholesterolemia, estrogen deficiency, or hyperinsulinemia. This clustering of risk factors greatly enhances the probability to develop atherosclerosis.³ Nevertheless, the cellular events responsible for the mutual appearance of several risk factors are poorly understood. A series of recent studies have addressed the hypothesis that enhanced AT₁ receptor activation could explain the association of various hormonal and metabolic disorders with hypertension, and ultimately, with accelerated progression of vascular lesions.

	Regulation of AT1 Receptor Expression and Function

 
As early as 1980, Alexander and colleagues discovered that the vasoconstriction caused by angiotensin II in resistance vessels was variable.⁴ Further investigations revealed that AT₁ receptor activation is subject to a negative feedback, in that increased levels of angiotensin II diminish and decreased angiotensin II concentrations enhance AT₁ receptor activation.^5–8 More recently, it has been shown that multiple agonists other than angiotensin II modulate AT₁ receptor expression. This phenomenon, referred to as heterologous AT₁ receptor regulation, is induced by various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), or fibroblast growth factor (FGF), all which downregulate AT₁ receptor expression.⁹ Numerous other factors, including glucocorticoids, aldosterone, forskolin, TNF, cytokines, nitric oxide, insulin, LDL, estrogen, progesterone, sodium, free radicals, . . . [Full Text of this Article]

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