title: Shear stress activation of SREBP1 in endothelial cells is mediated by integrins.
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/cm(2)) 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 (125)I-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 beta(1)-integrin with the AIIB2 blocking-type monoclonal antibody inhibited SREBP1 activation induced by shear stress. EC attachment to fibronectin or the activation of beta(1)-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.
authors.affiliation: Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California at San Diego, La Jolla, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Benjamin P-C
authors.initials: BP
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stemerman
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018056:Hemorheology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D017469:Receptors, Fibronectin; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases