Inhibition of PKC{beta}2 Overexpression Ameliorates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats via Restoring Caveolin-3/Akt Signaling

Activation of Protein Kinase Cβ (PKCβ) plays a critical role in myocardial ischemia/reperfusion (I/R) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 is overexpressed that is associated with increased vulnerability to post-ischemic I/R injury with concomitantly impaired cardiomyocyte caveolin (Cav)-3 and Akt signaling as compared with non- diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signaling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxistaurin (RBX, 1 mg/kg/day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding left descending coronary artery followed by reperfusion. Cardiac function was measured using pressure-volume conductance system. In in vitro study, cardiac H9C2 cells were exposed to high glucose (30 mmol/L) and subjected to hypoxia followed by reoxygenation (H/R) in the presence or absence of selective PKCβ2 inhibitor CGP53353 (1 µmol/L), siRNAs of PKCβ2 or Cav-3 or Akt. Cell apoptosis and mitochondrial membrane potential were assessed by TUNEL and JC-1 staining respectively. RBX significantly decreased post-ischemic myocardial infarct size (35±5% vs. 49±3% in control, P<0.05) and attenuated cardiac dysfunction, and prevented the reductions in cardiac Cav-3 and enhanced ph...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research