Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects
Article first published online: 29 JAN 2009
2006 British Pharmacological Society
British Journal of Pharmacology
Volume 149, Issue 1, pages 5–13, September 2006
How to Cite
Smith, C. C. T., Mocanu, M. M., Davidson, S. M., Wynne, A. M., Simpkin, J. C. and Yellon, D. M. (2006), Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. British Journal of Pharmacology, 149: 5–13. doi: 10.1038/sj.bjp.0706834
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received May 5, 2006, Revised May 31, 2006, Accepted June 14, 2006)
- myocardial ischaemia–reperfusion;
- mitochondrial permeability transition pore;
- p44/42 MAPK
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 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.
British Journal of Pharmacology (2006) 149, 5–13. doi:10.1038/sj.bjp.0706834