Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways

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 that was inhibited by preincubation with PD98059 and LY294002, suggesting that leptin mediated proliferation via extracellular signal-regulated kinase-1/2- and phosphatidylinositol-3-kinase-dependent signaling pathways. We confirmed that leptin activates both extracellular signal-regulated kinase-1/2 phosphorylation and association of phosphatidylinositol-3-kinase ( regulatory p85 subunit) with phosphotyrosine immunoprecipitates. We also examined bromodeoxyuridine incorporation as a measure of new DNA synthesis and demonstrated a stimulatory effect of leptin in both HL-1 cells and human cardiomyocytes. Bromodeoxyuridine incorporation in HL-1 cells was inhibited by PD98059 and LY294002. Our results establish a mitogenic effect of leptin in cardiomyocytes and provide additional evidence for a potential direct link between leptin and cardiac remodeling in obesity.