TY - JOUR T1 - Actin Cytoskeleton Dynamics Promotes Leptin-Induced Vascular Smooth Muscle Hypertrophy via RhoA/ROCK- and Phosphatidylinositol 3-Kinase/Protein Kinase B-Dependent Pathways JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1110 LP - 1116 DO - 10.1124/jpet.107.122440 VL - 322 IS - 3 AU - Asad Zeidan AU - Ben Paylor AU - Karly J. Steinhoff AU - Sabzali Javadov AU - Venkatesh Rajapurohitam AU - Subrata Chakrabarti AU - Morris Karmazyn Y1 - 2007/09/01 UR - http://jpet.aspetjournals.org/content/322/3/1110.abstract N2 - Obesity is associated with increased leptin production that may contribute to cardiovascular pathology through a multiplicity of effects. Leptin has been shown to contribute to vascular remodeling 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/Rho kinase (ROCK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways, actin dynamics, and the expression of serum-response factor (SRF) in the hypertrophic effects of leptin on vascular tissue. Strips of rat portal vein (RPV) were cultured with or without leptin at 3.1 nM for 1 to 3 days. Leptin significantly increased RhoA activity by 163 ± 20%, whereas phosphorylation of downstream factors, including LIM kinase 1 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 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). RhoA/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 that were significantly attenuated by a leptin receptor (leptin obese receptor) antibody, the ROCK inhibitor (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) (Y-27632) as well as the PI3K inhibitor LY294002. Our results indicate that the activation of RhoA/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. ER -