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1 Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States
2 Cardiothoracic Surgery, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States
3 Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem,, North Carolina, United States
* To whom correspondence should be addressed. E-mail: pkatakam{at}wfubmc.edu.
Insulin resistance (IR) precedes the onset of type 2 diabetes, but its impact on preconditioning against myocardial ischemia/reperfusion injury is unexplored. We examined the effects of diazoxide and ischemic preconditioning (IPC; 5 min ischemia and 5 min reperfusion) on ischemia (30 min)/reperfusion (240 min) injury in young IR Zucker obese (ZO) and lean (ZL) rats. ZO hearts developed larger infarcts than ZL hearts (infarct size: 57.3±3% in ZO versus 39.2±3.2% in ZL; p<0.05) and also failed to respond to cardioprotection by IPC or diazoxide (47.2 ± 4.3% and 52.5 ± 5.8% respectively, p=NS). In contrast, IPC and diazoxide treatment reduced the infarct size in ZL hearts (12.7 ± 2% and 16.3 ± 6.7% respectively, p<0.05). The mitochondrial KATP antagonist, 5-hydroxydecanoic acid, inhibited ischemic and diazoxide-induced preconditioning in ZL hearts while it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared to ZL (73±9% in ZL versus 39±9% in ZO, p<0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared to ZL. Electronmicrographs of ZO hearts revealed decreased number of mitochondria accompanied by swelling, disorganized cristae and vacuolation. Immunoblots of mitochondrial protein showed a modest increase in manganese superoxide dismutase in ZO. Thus, obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury that is likely to be mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial KATP .
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