Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis.
Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis.
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DOI：
10.1016/j.biocel.2011.10.011
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发表时间：
2012-01
影响因子：
4
通讯作者：
Sisson, Thomas H.
中科院分区：
文献类型：
--
作者：
Horowitz, Jeffrey C.;Ajayi, Iyabode O.;Kulasekaran, Priya;Rogers, David S.;White, Joshua B.;Townsend, Sarah K.;White, Eric S.;Nho, Richard S.;Higgins, Peter D. R.;Huang, Steven K.;Sisson, Thomas H.
肺和其他器官的纤维化以肌成纤维细胞的积累为特征，肌成纤维细胞是伤口修复的效应器，负责组织损伤后新细胞外基质（ECM）的沉积和组织。在正常伤口修复的分解阶段，肌成纤维细胞凋亡限制了ECM的持续沉积。越来越多的证据表明，来自纤维化伤口的肌成纤维细胞获得了对细胞凋亡的抗性，但调节这种抗性的机制尚未完全阐明。内皮素-1 （ET-1）是一种与纤维形成密切相关的可溶性肽，通过激活磷脂酰肌醇3 ' -OH激酶(PI3K)/AKT，降低肌成纤维细胞对凋亡的易感性。局灶黏附激酶（FAK）也通过PI3K/ akt依赖性和非依赖性机制促进肌成纤维细胞对凋亡的抵抗，尽管FAK在ET-1介导的细胞凋亡抵抗中的作用尚未被探索。本研究的目的是研究FAK是否参与ET-1介导的肌成纤维细胞对凋亡的抵抗，并研究FAK和PI3K/AKT下游ET-1调节肌成纤维细胞存活的潜在机制。在这里，我们发现ET-1通过Rho/ rock依赖性激活FAK来调节肌成纤维细胞的存活。反过来，FAK的抗凋亡作用依赖于PI3K/AKT的激活以及随后凋亡抑制蛋白（IAP）家族成员Survivin的表达增加。总的来说，这些研究确定了ET-1通过上调Survivin促进肌成纤维细胞抵抗凋亡的新机制。
Fibrosis of the lungs and other organs is characterized by the accumulation of myofibroblasts, effectors of wound-repair that are responsible for the deposition and organization of new extracellular matrix (ECM) in response to tissue injury. During the resolution phase of normal wound repair, myofibroblast apoptosis limits the continued deposition of ECM. Mounting evidence suggests that myofibroblasts from fibrotic wounds acquire resistance to apoptosis, but the mechanisms regulating this resistance have not been fully elucidated. Endothelin-1 (ET-1), a soluble peptide strongly associated with fibrogenesis, decreases myofibroblast susceptibility to apoptosis through activation of phosphatidylinositol 3′-OH kinase (PI3K)/AKT. Focal adhesion kinase (FAK) also promotes myofibroblast resistance to apoptosis through PI3K/AKT-dependent and – independent mechanisms, although the role of FAK in ET-1 mediated resistance to apoptosis has not been explored. The goal of this study was to investigate whether FAK contributes to ET-1 mediated myofibroblast resistance to apoptosis and to examine potential mechanisms downstream of FAK and PI3K/AKT by which ET-1 regulates myofibroblast survival. Here, we show that ET-1 regulates myofibroblast survival by Rho/ROCK-dependent activation of FAK. The anti-apoptotic actions of FAK are, in turn, dependent on activation of PI3K/AKT and the subsequent increased expression of Survivin, a member of the inhibitor of apoptosis protein (IAP) family. Collectively, these studies define a novel mechanism by which ET-1 promotes myofibroblast resistance to apoptosis through upregulation of Survivin.
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DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
影响因子：
20.1
作者：
Clemente, Carolina F. M. Z.;Tornatore, Thais F.;Franchini, Kleber G.
通讯作者：
Franchini, Kleber G.
DOI：
10.1165/rcmb.2005-0155oc
发表时间：
2006-03-01
影响因子：
6.4
作者：
Frankel, SK;Cosgrove, GP;Riches, DWH
通讯作者：
Riches, DWH
DOI：
10.3410/b2-78
发表时间：
2010-11-11
期刊：
F1000 biology reports
影响因子：
--
作者：
Hinz B;Gabbiani G
通讯作者：
Gabbiani G
影响因子：
20.1
作者：
Heidkamp, MC;Bayer, AL;Samarel, AM
通讯作者：
Samarel, AM