Shear stress activation of SREBP1 in endothelial cells is mediated by Integrins
Shear stress activation of SREBP1 in endothelial cells is mediated by Integrins
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DOI：
10.1161/hq0102.101822
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发表时间：
2002-01-01
影响因子：
8.7
通讯作者：
Shyy, JYJ
中科院分区：
文献类型：
--
作者：
Liu, Y;Chen, BPC;Shyy, JYJ
我们研究了剪切应力对血管内皮细胞（ECs）中固醇调节元件结合蛋白1 （SREBP1）的影响及其机械转导机制。施加剪切应力（12 dyn/cm(2)）导致SREBP1的蛋白水解裂解，其转录因子结构域随后易位到细胞核中。因此，剪切应力增加了编码低密度脂蛋白受体（LDLR）的mrna，以及I-125-LDL的结合。通过一个阶梯流动通道，我们发现SREBP1在层流条件下的激活是短暂的，但扰动的流动会导致持续的激活。在研究剪切应力诱导的激活SREBP1的分子信号时，我们发现用AIIB2阻断型单克隆抗体阻断β(1)-整合素可抑制剪切应力诱导的SREBP1激活。EC附着在纤维连接蛋白上或TS2/16单克隆抗体激活悬浮EC中的β(1)-整合素足以激活SREBP1。此外，瞬时转染实验表明，局灶黏附激酶和c-Src的显性阴性突变体减弱了剪切应力升高的LDLR启动子活性。这些结果表明，整合素信号在ECs对剪切应力的SREBP调节中起关键作用。
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 I-125-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.