Inhibition of PKCbeta2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling

Citation:

Y. Liu, J. Jin, S. Qiao, S. Lei, S. Liao, Z. D. Ge, H. Li, G. T. Wong, M. G. Irwin, and Z. Xia. 2015. “Inhibition of PKCbeta2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling.” Clin Sci (Lond)Clin Sci (Lond)Clin Sci (Lond), 129, Pp. 331-44.

Abstract:

Activation of PKCbeta (protein kinase Cbeta) plays a critical role in myocardial I/R (ischaemia/reperfusion) injury in non-diabetic rodents. In the myocardium of diabetes, PKCbeta2 overexpression is associated with increased vulnerability to post-ischaemic I/R injury with concomitantly impaired cardiomyocyte Cav (caveolin)-3 and Akt signalling compared with non-diabetic rats. We hypothesized that myocardial PKCbeta overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signalling. Streptozotocin-induced diabetic rats were treated with the selective PKCbeta inhibitor ruboxistaurin (RBX, 1 mg/kg per day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding the left descending coronary artery followed by reperfusion. Cardiac function was measured using a pressure-volume conductance system. In an 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 the selective PKCbeta2 inhibitor CGP53353 (1 mumol/l), siRNAs of PKCbeta2 or Cav-3 or Akt. Cell apoptosis and mitochondrial membrane potential were assessed by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) and JC-1 staining respectively. RBX significantly decreased post-ischaemic myocardial infarct size (35+/-5% compared with 49+/-3% in control, P<0.05) and attenuated cardiac dysfunction, and prevented the reduction in cardiac Cav-3 and enhanced phosphorylated/activated Akt (p-Akt) in diabetic rats (P<0.05). H/R increased cardiomyocyte injury under high glucose conditions as was evident by increased TUNEL-positive and increased JC-1 monomeric cells (P<0.05 compared with control), accompanied with increased PKCbeta2 phosphorylation/activation and decreased Cav-3 expression. Either CGP53353 or PKCbeta2 siRNA significantly attenuated all of these changes and enhanced p-Akt. Cav-3 gene knockdown significantly reduced p-Akt and increased post-hypoxic cellular and mitochondrial injury despite a concomitant reduction in PKCbeta2 phosphorylation. PKCbeta2 inhibition with RBX protects diabetic hearts from myocardial I/R injury through Cav-3-dependent activation of Akt.

Notes:

1470-8736Liu, YananJin, JiqinQiao, ShigangLei, ShaoqingLiao, SongyanGe, Zhi-DongLi, HaoboWong, Gordon Tin-ChunIrwin, Michael GXia, ZhengyuanJournal ArticleResearch Support, Non-U.S. Gov'tEnglandClin Sci (Lond). 2015 Aug;129(4):331-44. doi: 10.1042/CS20140789.