This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Shyy, J. Y.-J. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Shyy, J. Y.-J. Pubmed/NCBI databases Substance via MeSH Related Collections Pathophysiology Cell signalling/signal transduction Lipid and lipoprotein metabolism Endothelium/vascular type/nitric oxide

(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

This article has been cited by other articles:

				T. Petzold, A. W. Orr, C. Hahn, K. A. Jhaveri, J. T. Parsons, and M. A. Schwartz Focal adhesion kinase modulates activation of NF-{kappa}B by flow in endothelial cells Am J Physiol Cell Physiol, October 1, 2009; 297(4): C814 - C822. [Abstract] [Full Text] [PDF]

				Y. S. Chatzizisis, A. U. Coskun, M. Jonas, E. R. Edelman, C. L. Feldman, and P. H. Stone Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2379 - 2393. [Abstract] [Full Text] [PDF]

				X. Qin, J. Tian, P. Zhang, Y. Fan, L. Chen, Y. Guan, Y. Fu, Y. Zhu, S. Chien, and N. Wang Laminar shear stress up-regulates the expression of stearoyl-CoA desaturase-1 in vascular endothelial cells Cardiovasc Res, June 1, 2007; 74(3): 506 - 514. [Abstract] [Full Text] [PDF]

				S. Chien Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1209 - H1224. [Abstract] [Full Text] [PDF]

				J. Sanchez-Esteban, Y. Wang, E. J. Filardo, L. P. Rubin, and D. E. Ingber Integrins {beta}1, {alpha}6, and {alpha}3 contribute to mechanical strain-induced differentiation of fetal lung type II epithelial cells via distinct mechanisms Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L343 - L350. [Abstract] [Full Text] [PDF]

				A. Sasamoto, M. Nagino, S. Kobayashi, K. Naruse, Y. Nimura, and M. Sokabe Mechanotransduction by integrin is essential for IL-6 secretion from endothelial cells in response to uniaxial continuous stretch Am J Physiol Cell Physiol, May 1, 2005; 288(5): C1012 - C1022. [Abstract] [Full Text] [PDF]

				L. Zeng, H. Liao, Y. Liu, T.-S. Lee, M. Zhu, X. Wang, M. B. Stemerman, Y. Zhu, and J. Y.-J. Shyy Sterol-responsive Element-binding Protein (SREBP) 2 Down-regulates ATP-binding Cassette Transporter A1 in Vascular Endothelial Cells: A NOVEL ROLE OF SREBP IN REGULATING CHOLESTEROL METABOLISM J. Biol. Chem., November 19, 2004; 279(47): 48801 - 48807. [Abstract] [Full Text] [PDF]

				M. Yeh, A. L. Cole, J. Choi, Y. Liu, D. Tulchinsky, J.-H. Qiao, M. C. Fishbein, A. N. Dooley, T. Hovnanian, K. Mouilleseaux, et al. Role for Sterol Regulatory Element-Binding Protein in Activation of Endothelial Cells by Phospholipid Oxidation Products Circ. Res., October 15, 2004; 95(8): 780 - 788. [Abstract] [Full Text] [PDF]

				A. Katsumi, A. W. Orr, E. Tzima, and M. A. Schwartz Integrins in Mechanotransduction J. Biol. Chem., March 26, 2004; 279(13): 12001 - 12004. [Abstract] [Full Text] [PDF]

				P. A. VanderLaan, C. A. Reardon, and G. S. Getz Site Specificity of Atherosclerosis: Site-Selective Responses to Atherosclerotic Modulators Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 12 - 22. [Abstract] [Full Text] [PDF]

				T. Lin, L. Zeng, Y. Liu, K. DeFea, M. A. Schwartz, S. Chien, and J. Y.-J. Shyy Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins Circ. Res., June 27, 2003; 92(12): 1296 - 1304. [Abstract] [Full Text] [PDF]

				H. Wang, P. Maechler, P. A. Antinozzi, L. Herrero, K. A. Hagenfeldt-Johansson, A. Bjorklund, and C. B. Wollheim The Transcription Factor SREBP-1c Is Instrumental in the Development of beta -Cell Dysfunction J. Biol. Chem., May 2, 2003; 278(19): 16622 - 16629. [Abstract] [Full Text] [PDF]

				D. E. Ingber Tensegrity II. How structural networks influence cellular information processing networks J. Cell Sci., April 15, 2003; 116(8): 1397 - 1408. [Abstract] [Full Text] [PDF]

				D. E. Ingber Mechanical Signaling and the Cellular Response to Extracellular Matrix in Angiogenesis and Cardiovascular Physiology Circ. Res., November 15, 2002; 91(10): 877 - 887. [Abstract] [Full Text] [PDF]

				J. Y.-J. Shyy and S. Chien Role of Integrins in Endothelial Mechanosensing of Shear Stress Circ. Res., November 1, 2002; 91(9): 769 - 775. [Abstract] [Full Text] [PDF]