title: Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis.
abstract: 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.
authors: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, United States. jchorow@umich.edu
authors: Jeffrey C
authors: JC
authors: Horowitz
authors: Iyabode O
authors: IO
authors: Ajayi
authors: Priya
authors: P
authors: Kulasekaran
authors: David S
authors: DS
authors: Rogers
authors: Joshua B
authors: JB
authors: White
authors: Sarah K
authors: SK
authors: Townsend
authors: Eric S
authors: ES
authors: White
authors: Richard S
authors: RS
authors: Nho
authors: Peter D R
authors: PD
authors: Higgins
authors: Steven K
authors: SK
authors: Huang
authors: Thomas H
authors: TH
authors: Sisson
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D008168:Lung / Q000166:cytology; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000077022:Survivin; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D019332:Endothelin-1; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051058:Oncogene Protein v-akt; D054460:rho-Associated Kinases