Angiotensin Type I Receptor Blockade In Conjunction With Enhanced Akt Activation Restores Coronary Collateral Growth In The Metabolic Syndrome

Angiotensin Type I Receptor Blockade In Conjunction With Enhanced Akt Activation Restores Coronary Collateral Growth In The Metabolic Syndrome

Jadhav R; Dodd T; Smith E; Bailey E; DeLucia A L; Russell J C; Madison R; Potter B; Walsh K; Jo H J; Rocic P

American Journal of Physiology-Heart and Circulatory Physiology

2011

2011-05

Jadhav R, Dodd T, Smith E, Bailey E, DeLucia AL, Russell JC, Madison R, Potter B, Walsh K, Jo H, Rocic P. Angiotensin type I receptor blockade in conjunction with enhanced Akt activation restores coronary collateral growth in the metabolic syndrome. Am J Physiol Heart Circ Physiol 300: H1938-H1949, 2011. First published February 18, 2011; doi:10.1152/ajpheart.00282.2010.-We have previously demonstrated that Akt was required for repetitive ischemia (RI)-induced coronary collateral growth (CCG) in healthy rats but was not activated by RI in the metabolic syndrome (JCR:LA-cp rats) where CCG was impaired. Here we hypothesized that failure of angiotensin type I receptor (AT(1)R) blockers to restore Akt activation is a key determinant of their inability to completely restore CCG in the metabolic syndrome. Therefore, we investigated whether adenovirus-mediated delivery of constitutively active Akt (MyrAkt-Adv.) in conjunction with AT(1)R blockade (candesartan) was able to restore RI-induced CCG in JCR:LA-cp rats. Successful myocardial MyrAkt-Adv delivery was confirmed by a >80% transduction efficiency and an approximately fourfold increase in Akt expression and activation. CCG was assessed by myocardial blood flow measurements in the normal and collateral-dependent zones. MyrAkt-Adv alone significantly increased RI-induced CCG in JCR:LA-cp rats (similar to 30%), but it completely restored CCG in conjunction with administration of candesartan. In contrast, dominant negative Akt (DN-Akt-Adv) reversed the beneficial effect of candesartan on CCG in JCR:LA-cp rats. We conclude that optimal restoration of coronary collateral growth in JCR:LA-cp rats requires a combination of AT(1)R blockade with constitutive Akt activation. These findings may carry implications for metabolic syndrome patients in need of coronary revascularization.

Cardiovascular System & Cardiology; coronary artery occlusion; endothelial-cells; inhibition; ischemia-induced angiogenesis; kinase; mediated angiogenesis; nitric-oxide synthase; pathway; phosphorylation; Physiology; rat; smooth-muscle-cells; transient

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