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 language | English (US) |
---|---|
Pages (from-to) | 76-81 |
Number of pages | 6 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 22 |
Issue number | 1 |
DOIs | |
State | Published - 2002 |
Keywords
- Cholesterol
- Endothelial cells
- Integrins
- Shear stress
- Sterol regulatory element-binding protein 1
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine