Selective Inhibition of PKCβ2 Restores Ischemic Postconditioning-Mediated Cardioprotection by Modulating Autophagy in Diabetic Rats

Abstract

Diabetic hearts are more susceptible to myocardial ischemia/reperfusion (I/R) injury and less sensitive to ischemic postconditioning (IPostC), but the underlying mechanisms remain unclear. PKCβ2 is preferentially overactivated in diabetic myocardium, in which autophagy status is abnormal. This study determined whether hyperglycemia-induced PKCβ2 activation resulted in autophagy abnormality and compromised IPostC cardioprotection in diabetes. We found that diabetic rats showed higher cardiac PKCβ2 activation and lower autophagy than control at baseline. However, myocardial I/R further increased PKCβ2 activation and promoted autophagy status in diabetic rats. IPostC significantly attenuated postischemic infarct size and CK-MB, accompanied with decreased PKCβ2 activation and autophagy in control but not in diabetic rats. Pretreatment with CGP53353, a selective inhibitor of PKCβ2, attenuated myocardial I/R-induced infarction and autophagy and restored IPostC-mediated cardioprotection in diabetes. Similarly, CGP53353 could restore hypoxic postconditioning (HPostC) protection against hypoxia reoxygenation- (HR-) induced injury evidenced by decreased LDH release and JC-1 monomeric cells and increased cell viability. These beneficial effects of CGP53353 were reversed by autophagy inducer rapamycin, but could be mimicked by autophagy inhibitor 3-MA. It is concluded that selective inhibition of PKCβ2 could attenuate myocardial I/R injury and restore IPostC-mediated cardioprotection possibly through modulating autophagy in diabetes.

Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation

“…After development of a stable resting diameter (i.e., basal tone), the concentration-dependent vasoconstriction of coronary arterioles to PDBu was constructed and the involvements of PKC subtypes and Rho kinase were assessed with inhibitor Gö6983 (1 µmol/L) [ 79 ] against a broad-spectrum of PKC (PKCα, PKCβ, PKCγ, PKCδ and PKCζ), CGP53353 (0.3 µmol/L) against PKCβ2 [ 42 , 80 ], and Y27632 (0.1 µmol/L; Calbiochem, San Diego, CA, USA) against Rho kinase [ 20 ]. In another series of experiments, coronary arterioles were exposed to a sub-vasomotor level of PDBu (1 nmol/L) for 60 min and the vessels were challenged with the endothelium-dependent, NO-mediated vasodilators serotonin (0.1 nmol/L to 0.1 μmol/L) and adenosine (0.1 nmol/L to 10 μmol/L) and the endothelium-independent vasodilator sodium nitroprusside (0.1 nmol/L to 10 µmol/L).…”

Myocardial ischemia/reperfusion injury: Mechanisms of injury and implications for management (Review)

“…A recent study suggested that autophagy is necessary to decrease myocardial damage following acute myocardial ischemia and that autophagy limits activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome by removing damaged mitochondria ( 43 ). However, it is also reported that excessive autophagy during reperfusion may aggravate the injury of the heart ( 107 , 108 ).…”