Angiotensin type I receptor blockade in conjunction with enhanced Akt activation restores coronary collateral growth in the metabolic syndrome

作者：Jadhav Rashmi; Dodd Tracy; Smith Erika; Bailey Erin; DeLucia Angelo L; Russell James C; Madison Rowan; Potter Barry; Walsh Kenneth; Jo Hanjoong; Rocic Petra^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2011, 300(5): H1938-H1949.

DOI：10.1152/ajpheart.00282.2010

• transient
• coronary artery occlusion

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.

• 出版日期2011-5