The angiotensin II type 2 receptor in cardiovascular disease

Abstract

Angiotensin II (Ang II) is considered the major final mediator of the renin-angiotensin system. The actions of Ang II have been implicated in many cardiovascular conditions, such as hypertension, atherosclerosis, coronary heart disease, restenosis, and heart failure. Ang II can act through two different receptors: Ang II type 1 (AT1) receptor and Ang II type 2 (AT2) receptor. The AT1 receptor is ubiquitously expressed in the cardiovascular system and mediates most of the physiological and pathophysiological actions of Ang II. The AT2 receptor is highly expressed in the developing foetus, but its expression is very low in the cardiovascular system of the normal adult. Expression of the AT2 receptor can be modulated by pathological states associated with tissue remodelling or inflammation such as hypertension, atherosclerosis, and myocardial infarction. The precise role of the AT2 receptor remains under debate. However, it appears that the AT2 receptor plays a vasodilatory role, and may be enhanced as a countervailing mechanism in cardiac hypertrophy, and in presence of vascular injury in hypertension and atherosclerosis. Signalling pathways induced by the stimulation of the AT2 receptor are poorly understood, but three main mechanisms have been described: (a) activation of protein phosphatases causing protein dephosphorylation; (b) activation of bradykinin/nitric oxide/cyclic guanosine 3’,5’-monophosphate pathway; and (c) stimulation of phospholipase A2 and release of arachidonic acid. Vasodilatory effects of the AT2 receptor, probably the only well-established role of the AT2 receptor, have been attributed to the second of these mechanisms. The participation of the AT2 receptor in cardiovascular remodelling and inflammation is more controversial. In vitro, AT2 receptor stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, and stimulates apoptosis. In vivo, the situation is less clear, and depending on the studies, the AT2 receptor appears to be required for cardiac hypertrophic growth or contrariwise, the AT2 receptor has demonstrated no effects on cardiac hypertrophy. Similar controversial findings have been reported in atherosclerosis. Here we discuss the role of the AT2 receptor on cardiovascular structure and disease, and the signalling pathways induced by its activation.