| Disruption of Rac1 signaling reduces ischemia-reperfusion injury in the diabetic heart by inhibiting calpain. | |
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MedLine Citation:
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PMID: 20883775 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Diabetes increases myocardial ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remain incompletely understood. This study investigated the role of Rac1 signaling and calpain in exacerbated I/R injury in diabetic hearts. Mice with cardiac-specific deletion of Rac1 (Rac1-ko) and transgenic mice with cardiac-specific superoxide dismutase-2 (SOD2) or calpastatin overexpression were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to global I/R. After I/R, Rac1 activity was significantly enhanced in diabetic compared with nondiabetic hearts. Diabetic hearts displayed more severe I/R injury than nondiabetic hearts, as evidenced by more lactate dehydrogenase release and apoptosis and decreased cardiac function. These adverse impacts of diabetes were abrogated in Rac1-ko hearts or by perfusion with the Rac1 inhibitor NSC23766. In an in vivo I/R mouse model, infarct size was much smaller in diabetic Rac1-ko compared with wild-type mice. Inhibition of Rac1 signaling prevented NADPH oxidase activation, reactive oxygen species production, and protein carbonyl accumulation, leading to inhibition of calpain activation. Furthermore, SOD2 or calpastatin overexpression significantly reduced I/R injury in diabetic hearts and improved cardiac function after I/R. In summary, Rac1 activation increases I/R injury in diabetic hearts and the role of Rac1 signaling is mediated, at least in part, through calpain activation. |
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Authors:
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Limei Shan; Jianmin Li; Meng Wei; Jian Ma; Li Wan; Wei Zhu; Ying Li; Huaqing Zhu; J Malcolm O Arnold; Tianqing Peng |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-27 |
Journal Detail:
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Title: Free radical biology & medicine Volume: 49 ISSN: 1873-4596 ISO Abbreviation: Free Radic. Biol. Med. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-02 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8709159 Medline TA: Free Radic Biol Med Country: United States |
Other Details:
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Languages: eng Pagination: 1804-14 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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MOP93657//Canadian Institutes of Health Research |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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