Mineralocorticoid Receptor Antagonism Attenuates Vascular Apoptosis and Injury via Rescuing Akt Activation

Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure (BP)-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of BPlowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic BPs compared to Sprague-Dawley (SD) littermates, low dose spironolactone treatment did not reduce systolic BP compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with SD, and these abnormalities were attenuated by MR antagonism. Protein kinase B (Akt) activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Akt serine473 phosphorylation was impaired in Ren2 aortas, and restored with MR antagonism. In vivo MR antagonist treatment promoted anti-apoptotic effects by increasing phosphorylation of BAD serine136 and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor and MR, in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing Akt activation, independent of BP effects.