HSP70 increases extracellular matrix production by human vascular smooth muscle through TGF-β1 up-regulation
HSP70 increases extracellular matrix production by human vascular smooth muscle through TGF-β1 up-regulation
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DOI：
10.1016/j.biocel.2012.10.001
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发表时间：
2013-02-01
影响因子：
4
通讯作者：
Rodriguez-Puyol, Diego
中科院分区：
文献类型：
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作者：
Gonzalez-Ramos, Marta;Calleros, Laura;Rodriguez-Puyol, Diego
心血管疾病患者热休克蛋白（HSP）循环水平升高；然而，这对于这类疾病典型的纤维化过程的含义仍不清楚。HSP70可以通过toll样受体4 （TLR4）与血管平滑肌细胞（SMC）相互作用，SMC是细胞外基质（ECM）蛋白的主要产生者。转化生长因子- β 1 （tgf - β 1）是一种众所周知的血管促纤维化细胞因子，部分受ap -1依赖的转录机制调节。我们假设细胞外HSP70可以与SMCs相互作用，诱导tgf - β 1合成并随后改变血管ECM。我们证明细胞外HSP70与人主动脉SMCTLR4结合，上调tgf - β 1启动子的ap -1依赖性转录活性。这是通过丝裂原激活蛋白激酶JNK和ERK实现的，正如使用特异性阻断剂和用特异性小干扰rna敲低TLR4所证明的那样。tgf - β 1上调可增加ECM蛋白I型胶原蛋白和纤维连接蛋白的表达。这一新的观察结果可能阐明HSP70参与动脉粥样硬化和其他纤维化相关疾病的炎症和纤维化的机制。(C) 2012 Elsevier Ltd.版权所有。
The circulating levels of heat shock proteins (HSP) are increased in cardiovascular diseases; however, the implication of this for the fibrotic process typical of such diseases remains unclear. HSP70 can interact with the vascular smooth muscle cells (SMC), the major producer of extracellular matrix (ECM) proteins, through the Toll-like receptors 4 (TLR4). The transforming growth factor type-beta 1 (TGF-beta 1) is a well known vascular pro-fibrotic cytokine that is regulated in part by AP-1-dependent transcriptional mechanisms. We hypothesized that extracellular HSP70 could interact with SMCs, inducing TGF-beta 1 synthesis and subsequent changes in the vascular ECM. We demonstrate that extracellular HSP70 binds to human aorta SMCTLR4, which up-regulates the AP-1-dependent transcriptional activity of the TGF-beta 1 promoter. This is achieved through the mitogen activated protein kinases JNK and ERK, as demonstrated by the use of specific blockers and the knockdown of TLR4 with specific small interfering RNAs. The TGF-beta 1 upregulation increase the expression of the ECM proteins type I collagen and fibronectin. This novel observation may elucidate the mechanisms by which HSP70 contributes in the inflammation and fibrosis present in atherosclerosis and other fibrosis-related diseases. (C) 2012 Elsevier Ltd. All rights reserved.