The AT ₁ -Type Angiotensin Receptor in Oxidative Stress and Atherogenesis

Abstract

D espite 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 AT 1 receptor activation could explain the association of various hormonal and metabolic disorders with hypertension, and ultimately, with accelerated progression of vascular lesions. Regulation of AT 1 Receptor Expression and FunctionAs early as 1980, Alexander and colleagues discovered that the vasoconstriction caused by angiotensin II in resistance vessels was variable. 4 Further investigations revealed that AT 1 receptor activation is subject to a negative feedback, in that increased levels of angiotensin II diminish and decreased angiotensin II concentrations enhance AT 1 receptor activation. [5][6][7][8] More recently, it has been shown that multiple agonists other than angiotensin II modulate AT 1 receptor expression. This phenomenon, referred to as heterologous AT 1 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 AT 1 receptor expression. 9 Numerous other factors, including glucocorticoids, aldosterone, forskolin, TNF␣, cytokines, nitric oxide, insulin, LDL, estrogen, progesterone, sodium, free radicals, IGF-1, and isoprenaline are known to influence AT 1 receptor expression (Table). 10 -38 Hypercholesterolemia-Associated AT 1 Receptor OverexpressionHypercholesterolemia and in particular elevated LDL plasma concentrations play a fundamental role in the pathogenesis of atherosclerosis, as shown by numerous epidemiological and interventional studies. 1,2 Moreover, hypercholesterolemia is frequently associated with hypertension, another potent cardiovascular risk factor. 3 Despite this large body of epidemiological evidence, the molecular events leading from hypercholesterolemia to hypertension and atherosclerosis are only partially understood. Recent studies have provided insight into these interactions. For example, it has been shown that exposure of vascular smooth muscle cells to LDL markedly augments AT 1 receptor mRNA and protein expression. 39 Consistent with these findings, the functional response of these cells on angiotensin II stimulation (eg, calcium release, cell proliferation) is also enhanced. The underlying mechanism for this upregulation of...

Dyslipidemia and the Risk of Incident Hypertension in Men

“…Because atherosclerosis can be a diffuse process, it is possible that hypertension is a manifestation of a diffuse atherosclerotic process in large conduit arteries, as well as smaller resistance vessels. 4 Nickenig and Harrison 7,8 have linked lipids and hypertension via a mechanism of angiotensin I overexpression. Lipid abnormalities and insulin resistance have been associated with sympathetic hyperfunction, 25 which may play a role in the development of hypertension.…”

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

“…AT1 is constitutively expressed in placental VSMCs as shown in the Western blot data. AT1 plays important roles in angiogenic, inflammatory and oxidative stress responses in the placental vasculature [30][31][32][33]. A recent study by Herse et al showed that AT1 receptor mRNA expression was 10-fold higher in the placenta than in the decidua tissues in both normal and preeclamptic pregnancies, but no difference was noticed for AT1 mRNA expression between normal and preeclamptic placental tissues [34].…”

Modulation of the Inflammatory Response in Cardiovascular Disease

“…A key response of endothelial cells and inflammatory cells to Ang II is increased production of ROS and the consequent imbalance between ROS and NO. 47,52 This pro-oxidative effect of Ang II results from its engagement to the high-affinity angiotensin II type 1 (AT 1 ) receptor, which leads to the activation of NAD(P)H. 53 The proinflammatory AT 1 receptor is found on endothelial cells and circulating blood cells, including neutrophils, monocytes, T lymphocytes, and platelets. AT 1 receptor antagonists block the oxidative stress induced in these cells by Ang II.…”

“…54,55 The possibility that Ang II and AT 1 receptors are involved in eliciting the oxidative stress and leukocyte-endothelial cell adhesion of hypercholesterolemia is supported by studies of both large and microscopic blood vessels. 52,65 Furthermore, surrogate markers for endothelial activation and inflammation (eg, sVCAM-1) indicate that RAS-directed drugs might exert some of their beneficial effects by controlling the inflammatory response that accompanies CVD.…”