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


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.


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.


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.