title: Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation.
abstract: Myofibroblast apoptosis is critical for the normal resolution of wound repair responses, and impaired myofibroblast apoptosis is associated with tissue fibrosis. Lung expression of endothelin (ET)-1, a soluble peptide implicated in fibrogenesis, is increased in murine models of pulmonary fibrosis and in the lungs of humans with pulmonary fibrosis. Mechanistically, ET-1 has been shown to induce fibroblast proliferation, differentiation, contraction, and collagen synthesis. In this study, we examined the role ET-1 in the regulation of lung fibroblast survival and apoptosis. ET-1 rapidly activates the prosurvival phosphatidylinositol 3'-OH kinase (PI3K)/AKT signaling pathway in normal and fibrotic human lung fibroblasts. ET-1-induced activation of PI3K/AKT is dependent on p38 mitogen-activated protein kinase (MAPK), but not extracellular signal-regulated kinase (ERK) 1/2, JNK, or transforming growth factor (TGF)-beta1. Activation of the PI3K/AKT pathway by ET-1 inhibits fibroblast apoptosis, and this inhibition is reversed by blockade of p38 MAPK or PI3K. TGF-beta1 has been shown to attenuate myofibroblast apoptosis through the p38 MAPK-dependent secretion of a soluble factor, which activates PI3K/AKT. In this study, we show that, although TGF-beta1 induces fibroblast synthesis and secretion of ET-1, TGF-beta1 activation of PI3K/AKT is not dependent on ET-1. We conclude that ET-1 and TGF-beta1 independently promote fibroblast resistance to apoptosis through signaling pathways involving p38 MAPK and PI3K/AKT. These findings suggest the potential for novel therapies targeting the convergence of prosurvival signaling pathways activated by these two profibrotic mediators.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-5642, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Kulasekaran
authors.forename: Casey A
authors.initials: CA
authors.lastname: Scavone
authors.forename: David S
authors.initials: DS
authors.lastname: Rogers
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Arenberg
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D003513:Cycloheximide / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000473:pathology; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000196:embryology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D034421:Sus scrofa; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D003513:Cycloheximide; D019332:Endothelin-1; D053222:Fas Ligand Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; C494918:AKT1 protein, human