THE INFLUENCE OF AGTR1 IN THE DEVELOPMENT OF SYSTEMIC HYPERTENSION IN ATHEROSCLEROSIS

Abstract

The angiotensin II type 1 receptor (AT1R), encoded by the AGTR1 gene, is the principal effector of the renin angiotensin–aldosterone system (RAAS) and a central node linking systemic hypertension to atherosclerosis. Through Gq/11-, Gi- and β-arrestin-dependent signaling, activation of AT1R by angiotensin II (Ang II) in vascular smooth muscle cells, endothelial cells and immune cells promotes vasoconstriction, sodium retention, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated oxidative stress, inflammation, cellular proliferation and extracellular matrix remodeling. These processes simultaneously raise blood pressure and accelerate atherogenesis, so that hypertension and atherosclerosis frequently coexist and reinforce one another. The AGTR1 gene is polymorphic, and the A1166C variant (rs5186) in its 3′ untranslated region has been studied intensively; it disrupts a microRNA-155 binding site, thereby increasing receptor expression, and has been associated in several meta-analyses with essential hypertension, coronary artery disease and restenosis after coronary intervention, although effect sizes are modest and population-dependent. Experimental models demonstrate that AT1R activation in the vascular wall is necessary for Ang II-induced atherosclerosis and aneurysm formation, and that receptor blockade attenuates lesion development and endothelial dysfunction. Pharmacological antagonism of AT1R with angiotensin receptor blockers (ARBs) lowers blood pressure, reduces cardiovascular events and, in several imaging studies, slows the progression of carotid intima–media thickness, in part through effects that are independent of blood pressure reduction. In this review, we integrate the molecular biology of AT1R, the functional consequences of AGTR1 polymorphism, and the experimental and clinical evidence connecting AT1R signaling to the shared pathophysiology of hypertension and atherosclerosis, and we consider the therapeutic and future research implications.