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Cardiovasc Res. 2006 Feb 15;69(3):716-25. Epub 2005 Dec 22.

Direct effects of leptin on size and extracellular matrix components of human pediatric ventricular myocytes.

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1
Department of Biology, York University, Toronto, Canada M3J 1P3.

Abstract

OBJECTIVE:

There is a well-documented association between obesity and heart failure although the mechanistic basis for this correlation is unclear. Both extracellular matrix remodeling and left ventricular hypertrophy are well-defined components of remodeling in heart failure, and here we further investigate the role of leptin, the obese gene product, on these parameters.

METHODS:

We used primary human pediatric ventricular cardiomyocytes combined with gelatin zymography, quantitative PCR analysis, proline and leucine incorporation assays, and investigation of kinase activation by Western blotting.

RESULTS:

We show using gelatin zymography that leptin dose-dependently (0-60 nM) increased proteolytic activity at approximately 72 kDa. Accordingly, upon quantitative PCR analysis we found that leptin increased expression of matrix metalloproteinase-2 (MMP-2). Leptin also caused an increase in collagen type III and IV mRNA expression and a decrease in collagen type I mRNA expression. This was reflected in no significant change in total collagen synthesis, measured by [3H]proline incorporation, in response to leptin. A statistically significant increase in cell size, [3H]leucine incorporation, and expression of well-characterized markers of cardiac hypertrophy, namely cardiac alpha-actin and myosin light chain, were observed in response to leptin. We demonstrate activation of Janus-activated kinase and mitogen-activated protein kinase pathways by leptin, and using pharmacological inhibitors we show that these signaling pathways play a role in mediating the effects of leptin.

CONCLUSIONS:

Our findings show that leptin regulates cell size, stimulates MMP-2 expression, and alters the profile, but not the total content, of collagen in human cardiomyocytes. This indicates the potential for altered leptin sensitivity to directly regulate cardiac remodeling in obesity.

PMID:
16376323
DOI:
10.1016/j.cardiores.2005.11.022
[Indexed for MEDLINE]
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