Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice

Abstract

Ischemic postconditioning (IPCD) significantly reduces infarct size in healthy animals and protects the human heart. Because obesity is a major risk factor of cardiovascular diseases, the effects of IPCD were investigated in 8- to 10-wk-old leptin-deficient obese (ob/ob) mice and compared with wild-type C57BL/6J (WT) mice. All animals underwent 30 min of coronary artery occlusion followed by 24 h of reperfusion associated or not with IPCD (6 cycles of 10-s occlusion, 10-s reperfusion). Additional mice were killed at 10 min of reperfusion for Western blotting. IPCD reduced infarct size by 58% in WT mice (33+/-1% vs. 14+/-3% for control and IPCD, respectively, P<0.05) but failed to induce cardioprotection in ob/ob mice (53+/-4% vs. 56+/-5% for control and IPCD, respectively). In WT mice, IPCD significantly increased the phosphorylation of Akt (+77%), ERK1/2 (+41%), and their common target p70S6K1 (+153% at Thr389 and +57% at Thr421/Ser424). In addition, the phosphorylated AMP-activated protein kinase (AMPK)-to-total AMPK ratio was also increased by IPCD in WT mice (+64%, P<0.05). This was accompanied by decreases in phosphatase and tensin homolog deleted on chromosome 10 (PTEN), MAP kinase phosphatase (MKP)-3, and protein phosphatase (PP)2C levels. In contrast, IPCD failed to increase the phosphorylation state of all these kinases in ob/ob mice, and the level of the three phosphatases was significantly increased. Thus, although IPCD reduces myocardial infarct size in healthy animals, its cardioprotective effect vanishes with obesity. The lack of enhanced phosphorylation by IPCD of Akt, ERK1/2, p70S6K1, and AMPK might partly explain the loss of cardioprotection in this experimental model of obese mice.

Regular treadmill exercise restores cardioprotective signaling pathways in obese mice independently from improvement in associated co-morbidities

“…In parallel, the variations of phosphatase levels mirrored those of corresponding kinase phosphorylations as PTEN and MKP-3 were concomitantly decreased by regular exercise. This point is of major importance as it is known that phosphatases limit the efficacy of some cardioprotective strategies such as pre-or postconditioning during aging or obesity [9,29,30]. One could suggest that reduced phosphatases expression would be responsible for the activation of survival kinases which is known to be a crucial event for protecting the myocardium against myocardial infarction.…”

“…Indeed it has been previously reported that both pre-and postconditioning failed to reduce infarct size in obese animals probably because of their inability to activate the cardioprotective signalling pathways through kinase phosphorylations. [7][8][9]. Nevertheless, it is known that exercise is able to decrease cardiac events and mortality in obese or overweight patients [10][11][12].…”

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

“…Subsequent studies have confirmed the role for Akt and Erk1/2 in the setting of IPost in both non-diseased animal hearts and diseased ones [215,216] as well as human atrial muscle [217]. Interestingly, obese mice have been reported to be resistant to IPost protection, and this finding was associated with insufficient activation of the RISK pathway in the hearts harvested from obese animals compared to control ones [218]. This finding underscores the importance of using relevant experimental animal models capable of simulating disease pathologies present in patients with coronary heart disease.…”

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

“…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.…”