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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 6, 2005; DOI: 10.1124/jpet.105.091561

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Received for publication June 28, 2005.
Revised September 1, 2005.
Accepted for publication September 1, 2005.

Leptin Induces Vascular Smooth Muscle Cell Hypertrophy through Angiotensin II -and Endothelin-1 Dependent Mechanisms and Mediates Stretch-Induced Hypertrophy

Asad Zeidan 1, Daniel M Purdham 1, Venkatesh Rajapurohitam 1, Sabzali Javadov 1, Subrata Chakrabarti 1, Morris Karmazyn 1*

1 University of Western Ontario

* Address correspondence to: E-mail: morris.karmazyn{at}fmd.uwo.ca

Abstract

Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC) hypertrophy and elevated plasma leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of leptin and the effect of exogenous leptin (3.1 nM) on VSMC. Stretching the RPV significantly upregulated leptin production by greater than 100 fold and leptin receptor expression by up to 10 fold. In addition, stretch increased tissue weight by 23 ±; 1.3% and 30 ±; 1% (P<0.05) in the absence or presence of leptin, respectively although this was significantly attenuated by an anti-leptin antibody (166 ng/ml). Unstretched RPV weight decreased by 7.5 ±; 1.8% in the absence of leptin whereas in the presence of leptin weight increased by 6.5 ±; 1.8 % (P<0.05). VSMC size and [3H]leucine incorporation rates were significantly increased by leptin in stretched and unstretched tissues. Leptin-induced hypertrophy was associated with significant ERK1/2 activation as well as increased expression of angiotensinogen, the AT1 receptor as well as prepro endothelin-1 and the endothelin ETA receptor, whereas ERK inhibition or inhibition of either the angiotensin II or endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of leptin were also completely blocked by the cholesterol chelating agent methyl-{beta}-cyclodextrin. Our study therefore demonstrates stretch-dependent leptin release and a direct hypertrophic effect of leptin on RPV, the latter likely dependent on intact cholesterol-rich membrane microdomains and locally produced paracrine factors.


Key words: angiotension, caveolae, endothelin, hypertrophy, leptin, portal vein, rat


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