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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:76.)
© 2002 American Heart Association, Inc.

Vascular Biology

Shear Stress Activation of SREBP1 in Endothelial Cells Is Mediated by Integrins

Yi Liu; Benjamin P.-C. Chen; Min Lu; Yi Zhu; Michael B. Stemerman; Shu Chien; John Y.-J. Shyy

From the Department of Bioengineering and Whitaker Institute of Biomedical Engineering (B.P.-C.C., S.C.), University of California at San Diego, La Jolla, and the Division of Biomedical Sciences (Y.L., M.L., M.B.S., J.Y.-J.S.), University of California at Riverside.

Correspondence to John Y.-J. Shyy, PhD, Division of Biomedical Sciences, University of California at Riverside, Riverside, CA 92521-0121. E-mail john.shyy{at}ucr.edu

We investigated the effect of shear stress on the sterol regulatory element–binding protein 1 (SREBP1) in vascular endothelial cells (ECs) and the mechanotransduction mechanism involved. Application of a shear stress (12 dyn/cm²) caused the proteolytic cleavage of SREBP1 and the ensuing translocation of its transcription factor domain into the nucleus. As a result, shear stress increased the mRNAs encoding the low density lipoprotein receptor (LDLR), as well as the binding of ¹²⁵I-LDL. Using a step flow channel, we showed that SREBP1 activation in ECs under laminar flow is transient, but disturbed flow causes sustained activation. In studying the shear stress–elicited molecular signaling that activates SREBP1, we found that blocking the ß₁-integrin with the AIIB2 blocking-type monoclonal antibody inhibited SREBP1 activation induced by shear stress. EC attachment to fibronectin or the activation of ß₁-integrin in the suspended ECs by the TS2/16 monoclonal antibody was sufficient for SREBP1 activation. Furthermore, transient transfection assays showed that dominant-negative mutants of focal adhesion kinase and c-Src attenuated the shear stress–increased LDLR promoter activity. These results demonstrate that integrin signaling plays a critical role in the modulation of SREBP in ECs in response to shear stress.

Key Words: shear stress • sterol regulatory element–binding protein1 • integrins • endothelial cells • cholesterol

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