Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance

Abstract

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 vs. 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 = not significant). 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 ATP-activated potassium channel (K(ATP)) antagonist 5-hydroxydecanoic acid inhibited IPC and diazoxide-induced preconditioning in ZL hearts, whereas it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared with ZL (73 +/- 9% in ZL vs. 39 +/- 9% in ZO; P < 0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared with ZL hearts. Electron micrographs of ZO hearts revealed a 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 hearts. Thus obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury, which is mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial K(ATP).

Sevoflurane postconditioning against cerebral ischemic neuronal injury is abolished in diet-induced obesity: Role of brain mitochondrial KATP channels

“…By contrast, 5-HD did not change the infarct volume and functional deficits in the HF-fed rats following sevoflurane postconditioning. In addition, DZX, which has been used extensively to study pharmacological preconditioning to confer cardioprotection or neuroprotection by activating mitoK ATP channels (18,21), induced a similar significant reduction in the infarct volume and an improvement in functional deficits in the LF-fed rats, but not in the HF-fed rats, indicating that brain mitoK ATP channels were impaired …”

“…Mitochondria were isolated from brain tissue as previously described (18). Briefly, the brain tissue was homogenized (Glen Mills Inc., Clifton, NJ, USA) in ice cold isolation buffer containing 225 mmol/l mannitol, 75 mmol/l sucrose, 5 mmol/l 3-(N-morpholino)propanesulfonic acid (MOPS), 0.5 mmol/l EGTA and 2 mmol/l taurine, with 0.2% bovine serum albumin (BSA) (pH 7.25).…”

Mitochondrial dysfunction is induced by the overexpression of UCP4 in 3T3-L1 adipocytes

“…Mitochondrial morphology is closely related to mitochondrial function and metabolic activity (24). Several reports have described an association between mitochondrial dysfunction and alterations in mitochondrial morphology (25,26). The mitochondrial matrix and cristae are the main sites for metabolism, and condensed mitochondria do not contain enough space to maintain normal or super metabolic needs.…”

Myocardial Insulin Resistance: An Overview of Its Causes, Effects, and Potential Therapy

“…This is also supported by the recent findings of Bouhidel and co-workers [237] who reported impaired phosphorylation of Akt, Erk1/2 and p70S6K1 in ob/ob mice while others [236] presented evidence of impaired Erk1/2 activation and failure to phosphorylate and inactivate GSK3 . Ineffective protection in obese insulin resistance rats is also associated with impaired activation of the mitochondrial KATP channel [238]. All early indications suggest that distinct changes in intrinsic cardioprotective signalling occur in myocardial insulin resistance.…”

“…Wagner and co-workers [236] have shown loss of preconditioning in a rat model of established metabolic syndrome. In the leptin-deficient (ob/ob) mouse cardiac benefit from postconditioning is impaired [237], while there is also evidence of failed preconditioning in obese insulin-resistant rats [238]. Failure of a variety of cardioprotective interventions involving multiple and varied triggers, implicates dysfunction of the signalling paths of the RISK pathway that are common to these interventions.…”