Actin Cytoskeleton Dynamics Promotes Leptin-Induced Vascular Smooth Muscle Hypertrophy via RhoA/ROCK- and Phosphatidylinositol 3-Kinase/Protein Kinase B-Dependent Pathways
| Autor: | Karly J. Steinhoff, Venkatesh Rajapurohitam, Sabzali Javadov, Subrata Chakrabarti, Morris Karmazyn, Ben Paylor, Asad Zeidan |
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| Rok vydání: | 2007 |
| Předmět: |
Leptin
medicine.medical_specialty RHOA Vascular smooth muscle Protein Serine-Threonine Kinases Muscle Smooth Vascular Lim kinase Phosphatidylinositol 3-Kinases Internal medicine medicine Animals Rho-associated protein kinase Protein kinase B Cytoskeleton Pharmacology rho-Associated Kinases Leptin receptor biology Intracellular Signaling Peptides and Proteins Hypertrophy Actin cytoskeleton Actins Rats Endocrinology biology.protein Molecular Medicine rhoA GTP-Binding Protein Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 322:1110-1116 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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