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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1580    most recent 00379.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bouhidel, O. Articles by Ghaleh, B. PubMed PubMed Citation Articles by Bouhidel, O. Articles by Ghaleh, B.

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

¹Institut National de la Santé et de la Recherche Médicale U841, Equipe 3, ²Laboratoire de Pharmacologie, Faculté de Médecine, Université Paris 12, ³Groupe Henri Mondor-Albert Chenevier, Fédération de Cardiologie, and ⁴Plateforme Petit Animal, Institut Mondor de Médecine Moléculaire (IFR 10), Université Paris 12, Créteil, France

Submitted 13 April 2008 ; accepted in final form 6 August 2008

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.

infarction; obesity; kinase; phosphatase