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.
|Original language||English (US)|
|Number of pages||12|
|Journal||International Journal of Biochemistry and Cell Biology|
|State||Published - Jan 2012|
Bibliographical noteFunding Information:
These studies were supported by National Institutes of Health (NIH) grants K08 HL081059 (J.C.H.) and R01 HL105489 (J.C.H.) and funding from Atlantic Philanthropies Inc. (USA) , American College of Chest Physicians/The Chest Foundation , the John A. Hartford Foundation , and the Association of Specialty Professors (J.C.H.), NIH R01 HL078871 (T.H.S.), NIH R01 HL085083 (E.S.W.), and NIH K08 HL094657 (S.K.H.).
Copyright 2012 Elsevier B.V., All rights reserved.
- Focal adhesion kinase
- Inhibitor of apoptosis
- Mesenchymal cell