Published online before print May 29, 2003, doi: 10.1161/01.RES.0000078780.65824.8B
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins
From the Division of Biomedical Sciences (T.L., L.Z., Y.L., K.D., J.Y.-J.S.), University of California, Riverside, Calif; Division of Vascular Biology (M.A.S.), Department of Cell Biology, The Scripps Research Institute, La Jolla, Calif; and Department of Bioengineering and Whitaker Institute of Biomedical Engineering (S.C.), University of California, San Diego, La Jolla, Calif.
Correspondence to John Y.-J. Shyy, PhD, Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121. E-mail john.shyy{at}ucr.edu
Previous studies have shown that integrin activation and fluid shear stress can modulate the activity of sterol regulatory element binding proteins (SREBPs) in vascular endothelial cells. We investigated the role of small GTPase Rho-mediated signal transduction pathway in this mode of SREBP activation. Fluid shear stress activates the Rho downstream effectors ROCK, LIM kinase (LIMK), and cofilin. The various negative mutants of RhoA, ROCK, LIMK, and cofilin can block the shear stress activation of SREBPs. The shear stress–activated SREBP depends on S2P proteases but not caspase-3. Mechanistically, the endoplasmic reticulum-to-Golgi transport of SREBP cleavage–activating protein requires the actin-based cytoskeleton and is enhanced by the Rho-ROCK-LIMK-cofilin pathway. By enhancing the SREBP-mediated cholesterol metabolism, this unique mechanism may contribute to endothelial cell functions under flow.
Key Words: mechanotransduction • endothelial cells • sterol regulatory element binding proteins • shear stress • Rho
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