Disruption of Rac1 signaling reduces ischemia-reperfusion injury in the diabetic heart by inhibiting calpain.
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.
Shan
Limei
L
Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada.
Li
Jianmin
J
Wei
Meng
M
Ma
Jian
J
Wan
Li
L
Zhu
Wei
W
Li
Ying
Y
Zhu
Huaqing
H
Arnold
J Malcolm O
JM
Peng
Tianqing
T
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000235:genetics; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D013311:Streptozocin; D020744:rac GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology; D020830:rac1 GTP-Binding Protein
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D013311:Streptozocin; D002154:Calpain; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein