Activation of PKCβ (protein kinase Cβ) plays a critical role in myocardial I/R (ischaemia/reperfusion) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 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 PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signalling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ 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 PKCβ2 inhibitor CGP53353 (1 μmol/l), siRNAs of PKCβ2 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 PKCβ2 phosphorylation/activation and decreased Cav-3 expression. Either CGP53353 or PKCβ2 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 PKCβ2 phosphorylation. PKCβ2 inhibition with RBX protects diabetic hearts from myocardial I/R injury through Cav-3-dependent activation of Akt.
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May 21 2015
Inhibition of PKCβ2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling
Yanan Liu;
Yanan Liu
1
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
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Jiqin Jin;
Jiqin Jin
1
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
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Shigang Qiao;
Shigang Qiao
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
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Shaoqing Lei;
Shaoqing Lei
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
†Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
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Songyan Liao;
Songyan Liao
‡Department of Cardiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
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Zhi-Dong Ge;
Zhi-Dong Ge
§Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, U.S.A.
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Haobo Li;
Haobo Li
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
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Gordon Tin-chun Wong;
Gordon Tin-chun Wong
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
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Michael G. Irwin;
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
║Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, University of Hong Kong, Hong Kong SAR, China
Correspondence: Professor Michael Irwin (email [email protected]) or Dr Zhengyuan Xia (email [email protected]).
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Zhengyuan Xia
*Department of Anesthesiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China
║Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, University of Hong Kong, Hong Kong SAR, China
¶State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, University of Hong Kong, Hong Kong SAR, China
Correspondence: Professor Michael Irwin (email [email protected]) or Dr Zhengyuan Xia (email [email protected]).
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Publisher: Portland Press Ltd
Received:
December 01 2014
Revision Received:
March 30 2015
Accepted:
April 07 2015
Accepted Manuscript online:
April 07 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 129 (4): 331–344.
Article history
Received:
December 01 2014
Revision Received:
March 30 2015
Accepted:
April 07 2015
Accepted Manuscript online:
April 07 2015
Connected Content
Citation
Yanan Liu, Jiqin Jin, Shigang Qiao, Shaoqing Lei, Songyan Liao, Zhi-Dong Ge, Haobo Li, Gordon Tin-chun Wong, Michael G. Irwin, Zhengyuan Xia; Inhibition of PKCβ2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling. Clin Sci (Lond) 1 August 2015; 129 (4): 331–344. doi: https://doi.org/10.1042/CS20140789
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