Direct AT2 receptor stimulation is athero-protective and stabilizes plaque in Apolipoprotein E-deficient mice

Abstract Background The angiotensin II type 2 receptor (AT2 R) has been suggested to have an athero-protective role, however no studies have investigated the effect of direct stimulation of this receptor in atherosclerosis. Thus this study aimed to determine the effect of direct AT2 R stimulation in setting of atherosclerosis, using the known AT2 R agonist, CGP42112. Methods and results Apolipoprotein E-deficient (ApoE−/− ) mice were fed a high fat (21%) diet for 16 weeks, with subcutaneous infusions of CGP42112 (1, 5 or 10 μg/kg/min) administered via osmotic mini-pumps in the final 4 weeks. CGP42112 treatment at all doses significantly improved endothelial function (p < 0.001) when compared to acetylcholine mediated-vasorelaxation in aorta taken from vehicle-treated ApoE−/− mice. In aortic segments adjacent to those used for vascular reactivity studies, CGP42112 treatment at all doses concomitantly increased eNOS immunoreactivity and protein levels whilst superoxide (O2− ) production was significantly (p < 0.01) decreased compared to levels measured in aorta from vehicle-treated ApoE−/− mice. Moreover, CGP42112 (1 μg/kg/min) treatment significantly attenuated (p < 0.05) atherosclerotic lesion progression (assessed as both lipid deposits and luminal encroachment in thoracic aorta and aortic arch) and significantly increased plaque stability in the brachiocephalic artery, a region normally prone to rupture. Both the vaso- and athero-protective effects of CGP42112 (1 μg/kg/min) were reversed with co-infusion of the AT2 R antagonist, PD123319, but not the Mas R antagonist, A779. Conclusion For the first time we have shown that direct stimulation of the AT2 R improves endothelial function, reduces atherosclerotic lesion progression and mediates plaque stability with these effects at least partly due to restoration of nitric oxide bioavailability.