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

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

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 β1-integrin with the AIIB2 blocking-type monoclonal antibody inhibited SREBP1 activation induced by shear stress. EC attachment to fibronectin or the activation of β1-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.

Original languageEnglish (US)
Pages (from-to)76-81
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume22
Issue number1
DOIs
StatePublished - Jan 29 2002

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Keywords

  • Cholesterol
  • Endothelial cells
  • Integrins
  • Shear stress
  • Sterol regulatory element-binding protein 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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