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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 723974.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension
Authors:Kovacs, L.; Han, W.; Rafikov, R.; Bagi, Z.; Offermanns, S.; Saido, T. C.; Black, S. M.; Su, Y.
Date of Publication (YYYY-MM-DD):2015-08-06
Title of Journal:Am J Respir Cell Mol Biol
Audience:Not Specified
Abstract / Description:Calpain mediates the collagen synthesis and cell proliferation and plays an important role in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). In the present study, we investigate whether and how calpain is activated by PAH mediators in pulmonary artery smooth muscle cells (PASMCs). These data showed that smooth muscle-specific knockout of calpain attenuated and knockout of calpastatin potentiated pulmonary vascular remodeling and pulmonary hypertension. Treatment of PASMCs with the PAH mediators platelet-derived growth factor (PDGF), serotonin, H2O2, endothelin-1 and interleukin-6 caused significant increases in calpain activity, cell proliferation, and collagen-I protein level without changes in protein levels of calpain-1 and -2. The calcium chelator BAPTA/AM did not affect calpain activation but the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 and knocking down of calpain-2 prevented calpain activation in PAH mediator-treated PASMCs. Mass spectrometry data showed that the phosphorylation of calpain-2 at serine 50 (Ser50) was increased and the phosphorylation of calpain-2 at serine 369 (Ser369) was decreased in PDGF-treated PASMCs. The PDGF-induced increase in Ser50 phosphorylation of calpain-2 was prevented by the ERK1/2 inhibitor PD98059, while dephosphorylation of calpain-2 at Ser369 was blocked by the protein phosphatase 2A (PP2A) inhibitor fostriecin. Furthermore, smooth muscle of pulmonary arteries in PAH animal model and PAH patients showed higher levels of P-Ser50-calpain-2 and lower levels of P-Ser369-calpain-2. These data support that calpain modulates pulmonary vascular remodeling in PAH. PAH mediator-induced activation of calpain is caused by ERK1/2-dependent phosphorylation of calpain-2 at Ser50 and PP2A-dependent dephosphorylation of calpain-2 at Ser369 in pulmonary vascular remodeling of PAH.
Free Keywords:5-ht; Et-1; Pdgf; Pulmonary hypertension; vascular smooth muscle
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Georgia Regents University, Pharmacology, Augusta, Georgia, United States ; whan@gru.edu. Georgia Regents University, Vacular Biology Center, Augusta, Georgia, United States ; rrafikov@gru.edu. Georgia Regents University, Vacular Biology Center, Augusta, Georgia, United States ; ZBagi@gru.edu. Goethe University, Max Planck Institute for Heart and Lung Research, Frankfurt, Germany ; Stefan.Offermanns@mpi-bn.mpg.de. RIKEN Brain Institute, Laboratory for Proteolytic Neuroscience, Saitama, Japan ; saido@brain.riken.jp. Georgia Regents University, Vacular Biology Center, Augusta, Georgia, United States ; SBLACK@gru.edu. Georgia Regents University, Department of Pharmacology & Toxicology, Augusta, Georgia, United States ; ysu@gru.edu.
Identifiers:ISSN:1535-4989 (Electronic) 1044-1549 (Linking) %R 10.1165/rcmb.2015-0151OC
URL:http://www.ncbi.nlm.nih.gov/pubmed/26248159
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