Yanan Liu1, Jiqin Jin1, Shigang Qiao1, Songyan Liao1, Zhi-Dong Ge2, Michael G Irwin1 and Zhengyuan Xia1
1University of Hong Kong, China 2The Medical College of Wisconsin, USA
Posters-Accepted Abstracts: J Diabetes Metab
Background: Activation of PKCβ has been shown to exacerbate myocardial ischemia/reperfusion (I/R) injury. Caveolin-3 (Cav-3) specifically expressed in cardiomyocytes is critical in signal transduction of PKCβ in cardiomyocytes. The present study tested the hypothesis that ruboxistaurin (RBX), a selective PKCβ inhibitor, may attenuate myocardial I/R injury in Diabetes through a Cav-3- dependent mechanism. Methods: Sprague-Dawley rats were treated with RBX (1 mg/kg/day) for 4 weeks, starting from 1 week after streptozotocin injection. Diabetic hearts were subjected to I/R achieved by the left descending coronary artery ligation followed by reperfusion. Cardiac function was measured using a pressure-volume conductance catheter. Cardiac H9C2 cells were exposed to high glucose (30mM) and subjected to hypoxia followed by reoxygenation (H/R) in the presence or absence of PKCβ2 siRNA and Cav-3 siRNA. Cell apoptosis and mitochondrial injury were assessed by TUNEL and JC-1 staining respectively. Results: RBX significantly decreased myocardial infarct size from 35±5% in the control groups to 49±3% and cardiac dysfunction and increased Cav-3 and phosphorylated Akt (p-Akt) in diabetic rats (All P<0.05 vs. control). PKCβ2 siRNA significantly decreased H/R-induced H9C2 cell injury in vitro under high glucose conditions evidenced as decreased TUNEL-positive and JC-1 monomeric cells, whereas Cav-3 siRNA significantly increased H/R-induced H9C2 cell injury (All P<0.05 vs. control). Interestingly, Cav-3 siRNA significantly reduced p-Akt and increased post-hypoxic mitochondrial injury, concomitantly with a reduction in PKCβ2 phosphorylation. Conclusions: PKCβ2 plays an obligatory role in myocardial I/R injury in Diabetes. The Cav-3-dependent Akt activation contributes to RBX-induced cardio protection against I/R.
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