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Submitted on August 28, 2003
Accepted on December 29, 2003
Department of Biology, York University, Toronto and Toronto General Research Institute, Toronto General Hospital, Canada.
* To whom correspondence should be addressed. E-mail: gsweeney{at}yorku.ca.
Obesity is a major risk factor for the development of heart failure. Importantly, it is now appreciated that a change in the number of myocytes is one of multiple structural and functional alterations (remodeling) leading to heart failure. Here we investigate the effect of leptin, the product of the obese (ob) gene, on proliferation of human and murine cardiomyocytes. Leptin caused a time- and dose-dependent significant increase in proliferation of HL-1 cells which was inhibited by preincubation with PD98059 and LY294002, suggesting that leptin mediated proliferation via ERK1/2- and PI 3-kinase-dependent signaling pathways. We confirmed that leptin activates both ERK1/2 phosphorylation and association of PI 3-kinase (regulatory p85 subunit) with phosphotyrosine immunoprecipitates. We also examined bromodeoxyuridine (BrdU) incorporation as a measure of new DNA synthesis and demonstrated a stimulatory effect of leptin in both HL-1 cells and human cardiomyocytes. BrdU incorporation in HL-1 cells was inhibited by PD98059 and LY294002. Our results establish a mitogenic effect of leptin in cardiomyocytes and provide further evidence for a potential direct link between leptin and cardiac remodeling in obesity.
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