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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 7, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn158
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Rho-GDI{alpha} Downregulated by Low Shear Stress Promotes Vascular Smooth Muscle Cell Migration and Apoptosis: A Proteomic Analysis

Ying-Xin Qi1, Ming-Juan Qu1, Ding-Kun Long1, Bo Liu1, Qing-Ping Yao1, Shu Chien1,2 and Zong-Lai Jiang1,*

1 Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
2 Departments of Bioengineering and Medicine, University of California, San Diego, La Jolla, CA 92093-0412, USA

* Please address correspondence to: Dr. Zonglai Jiang, Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, P.O.Box 888, Shanghai Jiao Tong University 800 Dongchuan Road Minhang, Shanghai 200240 China Tel: +86-21-34204863 Fax: +86-21-34204118 e-mail: zljiang{at}sjtu.edu.cn

Aim: Low shear stress (LSS) plays a significant role in vascular remodeling during atherogenesis, which involves migration, proliferation and apoptosis of vascular smooth muscle cells (VSMCs). The aim of the present study is to elucidate the molecular mechanisms by which LSS induces vascular remodeling.

Methods and Results: Using proteomic techniques, two-dimensional electrophoresis and mass spectrometry, the protein profiles of Sprague-Dawley rat aorta cultured under two levels of shear stress, 5 and 15 dyn/cm2, were determined. The results showed a significantly lower expression of protein-Rho-GDP dissociation inhibitor alpha (Rho-GDI{alpha}) in the LSS vessels. Rho-GDI{alpha} signaling mechanisms and effects on VSMC migration and apoptosis were then studied to understand the role of Rho-GDI{alpha} in the LSS-induced vascular remodeling. A decrease in Rho-GDI{alpha} expression by using target small interfering RNA (siRNA) transfection caused increases in the phosphorylation of Rac1 and Akt and enhancements of VSMC migration and apoptosis. Treatment with the PI3K/Akt-specific inhibitor wortmannin significantly decreased Akt phosphorylation, but had no effect on Rho-GDI{alpha} expression and Rac1 phosphorylation. Wortmannin was able to reverse the Rho-GDI{alpha} siRNA-induced enhancement of VSMC migration, but not VSMC apoptosis.

Conclusions: The results indicate that the LSS-induced VSMC migration and apoptosis are mediated by a downregulation of Rho-GDI{alpha}. The effect of Rho-GDI{alpha} on VSMC migration is mediated by the PI3K/Akt pathway, but its effect on VSMC apoptosis is not.

KEYWORDS Rho-GDI{alpha}; migration; apoptosis; vascular smooth muscle cells; shear stress

Time for primary review: 22 days


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