Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects

被引:130
作者
Smith, C. C. T.
Mocanu, M. M.
Davidson, S. M.
Wynne, A. M.
Simpkin, J. C.
Yellon, D. M.
机构
[1] UCL Hosp, Hatter Cardiovasc Inst, London WC1E 6HX, England
[2] Sch Med, London WC1E 6HX, England
关键词
leptin; myocardial ischaemia -reperfusion; cardiomyocytes; mitochondrial permeability transition pore; Akt; p44/; 42; MAPK;
D O I
10.1038/sj.bjp.0706834
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background and purpose: Protection against ischaemia-reperfusion (I/R) injury involves PI3K-Akt and p44/42 MAPK activation. Leptin which regulates appetite and energy balance also promotes myocyte proliferation via PI3K-Akt and p44/42 MAPK activation. We, therefore, hypothesized that leptin may also exhibit cardioprotective activity. Experimental approach: The influence of leptin on I/R injury was examined in perfused hearts from C57BI/6J mice that underwent 35 min global ischaemia and 35 min reperfusion, infarct size being assessed by triphenyltetrazolium chloride staining. The concomitant activation of cell-signalling pathways was investigated by Western blotting. The effect of leptin on mitochondrial permeability transition pore (MPTP) opening was studied in rat cardiomyocytes. Key results: Leptin (10 nM) administered during reperfusion reduced infarct size significantly. Protection was blocked by either LY294002 or UO126, inhibitors of Akt and p44/42 MAPK, respectively. Western blotting confirmed that leptin stimulated p44/42 MAPK phosphorylation significantly. Akt phosphorylation was also enhanced but did not achieve statistical significance. Additionally, leptin treatment was associated with a significant increase in p38 phosphorylation. By contrast, leptin caused downregulation of phosphorylated and non-phosphorylated STAT3, and of total AMP-activated kinase. Cardiomyocytes responded to leptin with delayed opening of the MPTP and delayed time until contracture. Conclusions and implications: Our data indicate for the first time that the adipocytokine, leptin, has direct cardioprotective properties which may involve the PI3-Akt and p44/42 MAPK pathways.
引用
收藏
页码:5 / 13
页数:9
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