Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 49, Issue 11, Pages 1804-1814Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.09.018
Keywords
Rac1; Reactive oxygen species; Calpain; Diabetes; Ischemia; Reperfusion; Free radicals
Funding
- Heart & Stroke Foundation of Ontario [NA6315]
- Canadian Institutes of Heart Research [MOP93657]
- Heart & Stroke Foundation of Canada
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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 Rad signaling and calpain in exacerbated I/R injury in diabetic hearts Mice with cardiac specific deletion of Rac1 (Rad 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 Rad 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 Rad signaling is mediated at least in part through calpain activation (C) 2010 Elsevier Inc All rights reserved
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