Abstract
Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Actin Cytoskeleton / metabolism
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Active Transport, Cell Nucleus
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Animals
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Apoptosis / drug effects
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Cell Differentiation
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Extracellular Matrix / metabolism
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Female
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Humans
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Mechanotransduction, Cellular*
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Mice
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Mice, Inbred C57BL
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Molecular Targeted Therapy
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Myofibroblasts / drug effects
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Myofibroblasts / metabolism
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Myofibroblasts / physiology*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Protein Multimerization
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / drug therapy
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Pulmonary Fibrosis / metabolism
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Pulmonary Fibrosis / pathology*
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Trans-Activators
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Transforming Growth Factor beta1 / physiology
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rho GTP-Binding Proteins / metabolism
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rho-Associated Kinases / antagonists & inhibitors
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rho-Associated Kinases / metabolism
Substances
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DNA-Binding Proteins
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MRTFA protein, human
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins c-bcl-2
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Trans-Activators
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Transforming Growth Factor beta1
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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rho-Associated Kinases
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rho GTP-Binding Proteins
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fasudil