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Link to original content: https://pubmed.ncbi.nlm.nih.gov/16847434/
Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects - PubMed Skip to main page content
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. 2006 Sep;149(1):5-13.
doi: 10.1038/sj.bjp.0706834. Epub 2006 Jul 17.

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

C C T Smith  1 , M M Mocanu, S M Davidson, A M Wynne, J C Simpkin, D M Yellon
Affiliations

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

C C T Smith et al. Br J Pharmacol. 2006 Sep.

Abstract

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.

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Figures

Figure 1
Figure 1
Infarct size, as a percentage of the risk zone (% I/R), in isolated mouse hearts perfused with or without leptin (10 nM) during reperfusion (35 min) in the presence or absence of LY294002 or UO126, inhibitors of PI3K and p44/42 MAPK, respectively. Values are expressed as means±s.e.m. of 4–12 experiments (***P<0.01 vs control).
Figure 2
Figure 2
Total and phosphorylated Akt in tissue extracts from hearts subjected to ischaemia–reperfusion. Data are presented as relative densitometry (RD) values in a.u. normalized for β-actin. Values are expressed as mean±s.e.m. (‡P<0.001, LY vs control and **P<0.02, leptin+LY vs leptin; n=5).
Figure 3
Figure 3
Total and phosphorylated p44/42 MAPK in tissue extracts from hearts subjected to ischaemia–reperfusion. Data are shown as RD values (a.u.) normalized for β-actin loading and show that leptin stimulates p44/42 MAPK (a) and p42 (b) phosphorylation, which is blocked by UO126. Values are presented as mean±s.e.m. (*P<0.05 and **P<0.02, leptin vs control and ‡P<0.001, leptin+UO vs leptin; n=4–5).
Figure 4
Figure 4
Total and phosphorylated p38 MAPK in tissue extracts from hearts subjected to ischaemia–reperfusion. Data are shown as RD values (a.u.) normalized for β-actin loading and show that leptin stimulates p38 MAPK phosphorylation. Values are presented as mean±s.e.m. (*P<0.05 vs control; n=5).
Figure 5
Figure 5
Total and phosphorylated STAT3 in tissue extracts from hearts subjected to ischaemia–reperfusion. Data are shown as RD values (a.u.) normalized for β-actin loading and indicate that leptin induces downregulation of both phosphorylated (a) and total STAT3 (b), which is reversed by UO126. Values are presented as mean± s.e.m. (†P<0.01 and ‡P<0.001 vs control, and *P<0.05, leptin+UO vs leptin; n=4–5).
Figure 6
Figure 6
Total and phosphorylated AMPK in tissue extracts following ischaemia–reperfusion. Data are shown as RD values (a.u.) normalized for β-actin loading and indicate that leptin induces downregulation of both phosphorylated (a) and total AMPK (b), which is reversed by UO126. Values are presented as mean±s.e.m. (***P<0.01 vs control; n=4–5).
Figure 7
Figure 7
The times until the initiation of mitochondrial depolarization, that is, MPTP opening (a) and cardiomyocyte contracture (b) in the presence and absence of leptin with or without LY294002 or MEK inhibitor 1 (MEKi), inhibitors of PI3K and p44/42 MAPK, respectively. Data are presented as means±s.e.m. (*P<0.05 and ‡P<0.001 vs control) and were obtained with a total of 19–51 cells from at least three hearts.
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