Rac1 Is Required for Cardiomyocyte Apoptosis During Hyperglycemia
- E. Shen1,2,
- Yanwen Li3,
- Ying Li1,2,
- Limei Shan1,2,
- Huaqing Zhu1,2,
- Qingping Feng1,2,4,
- J. Malcolm O. Arnold1,2,4 and
- Tianqing Peng1,2,5
- 1Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada;
- 2Department of Medicine, University of Western Ontario, London, Ontario, Canada;
- 3Department of Microbiology, Imperial College London, London, U.K;
- 4Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada;
- 5Department of Pathology, University of Western Ontario, London, Ontario, Canada.
- Corresponding author: Tianqing Peng, tpeng2{at}uwo.ca.
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E.S. and Y.L. contributed equally to this study.
Abstract
OBJECTIVE Hyperglycemia induces reactive oxygen species (ROS) and apoptosis in cardiomyocytes, which contributes to diabetic cardiomyopathy. The present study was to investigate the role of Rac1 in ROS production and cardiomyocyte apoptosis during hyperglycemia.
RESEARCH DESIGN AND METHODS Mice with cardiomyocyte-specific Rac1 knockout (Rac1-ko) were generated. Hyperglycemia was induced in Rac1-ko mice and their wild-type littermates by injection of streptozotocin (STZ). In cultured adult rat cardiomyocytes, apoptosis was induced by high glucose.
RESULTS The results showed a mouse model of STZ-induced diabetes, 7 days of hyperglycemia-upregulated Rac1 and NADPH oxidase activation, elevated ROS production, and induced apoptosis in the heart. These effects of hyperglycemia were significantly decreased in Rac1-ko mice or wild-type mice treated with apocynin. Interestingly, deficiency of Rac1 or apocynin treatment significantly reduced hyperglycemia-induced mitochondrial ROS production in the heart. Deficiency of Rac1 also attenuated myocardial dysfunction after 2 months of STZ injection. In cultured cardiomyocytes, high glucose upregulated Rac1 and NADPH oxidase activity and induced apoptotic cell death, which were blocked by overexpression of a dominant negative mutant of Rac1, knockdown of gp91phox or p47phox, or NADPH oxidase inhibitor. In type 2 diabetic db/db mice, administration of Rac1 inhibitor, NSC23766, significantly inhibited NADPH oxidase activity and apoptosis and slightly improved myocardial function.
CONCLUSIONS Rac1 is pivotal in hyperglycemia-induced apoptosis in cardiomyocytes. The role of Rac1 is mediated through NADPH oxidase activation and associated with mitochondrial ROS generation. Our study suggests that Rac1 may serve as a potential therapeutic target for cardiac complications of diabetes.
Footnotes
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E.S. is currently affiliated with The 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received May 7, 2008.
- Accepted July 1, 2009.
- © 2009 by the American Diabetes Association.
