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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 11, 2007; DOI: 10.1124/jpet.107.122440

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Received for publication March 8, 2007.
Revised June 8, 2007.
Accepted for publication June 8, 2007.

Actin Cytoskeleton Dynamics Promote Leptin-Induced Vascular Smooth Muscle Hypertrophy via Rho/ROCK and PI3K/Akt Dependent Pathways

Asad Zeidan 1, Ben Paylor 1, Karly J Steinhoff 1, Sabzali Javadov 1, Venkatesh Rajapurohitam 1, Subrata Chakrabarti 1, Morris Karmazyn 1*

1 University of Western Ontario

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

Abstract

Obesity is associated with increased leptin production which may contribute to cardiovascular pathology through a multiplicity of effects. Leptin has been shown to contribute to vascular remodelling through various mechanisms including production of vascular smooth muscle (VSMC) hypertrophy, however the mechanisms underlying the vascular hypertrophic effect of leptin remain unknown. In the present study we investigated the contributions of the RhoA/ROCK and PI3K/Akt pathways, actin dynamics, and the expression of serum response factor (SRF) in the hypertrophic effects of leptin vascular tissue. Strips of rat portal vein (RPV) were cultured with or without leptin (3.1 nmol/L) for 1-3 days. Leptin significantly increased RhoA activity by 163±20%, whereas phosphorylation downstream factors including LIMK1 and cofilin-2 was increased by 160±25% and 290±25% respectively. Leptin also significantly phosphorylated Akt by 130±30% which was inhibited by the PI3K inhibitor LY294002. Rho/ROCK and PI3K/Akt activation was associated with a significant increase in RPV wet weight (11±1%), protein synthesis (45±7%), SRF expression (136±11%) and polymerization of actin, as reflected by an increase in the F/G actin ratio, effects which were significantly attenuated by a leptin receptor (OBR) antibody, the ROCK inhibitor Y-27632 as well as the PI3K inhibitor LY294002. Our results indicate that the activation of Rho/ROCK and PI3K/Akt plays a pivotal role in leptin signaling leading to the development of VSMC hypertrophy through a mechanism involving altered actin dynamics.


Key words: Hypertrophy, Leptin, PI3K/Akt, Portal vein, RhoA/ROCK, serum response factor


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