Premium
Leptin, the obesity‐associated hormone, exhibits direct cardioprotective effects
Author(s) -
Smith C C T,
Mocanu M M,
Davidson S M,
Wynne A M,
Simpkin J C,
Yellon D M
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706834
Subject(s) - leptin , protein kinase b , endocrinology , medicine , mapk/erk pathway , phosphorylation , pi3k/akt/mtor pathway , chemistry , signal transduction , biochemistry , obesity
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 C57Bl/6 J 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 n M ) 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. British Journal of Pharmacology (2006) 149 , 5–13. doi: 10.1038/sj.bjp.0706834