title: Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts.
abstract: Although cardiac fibrosis causes heart failure, its molecular mechanisms remain elusive. In this study, we investigated the mechanisms of cardiac fibrosis and examined the effects of the antifibrotic drug pirfenidone (PFD) on chronic heart failure. To understand the responsible mechanisms, we generated an in vivo pressure-overloaded heart failure model via transverse aortic constriction (TAC) and examined the effects of PFD on chronic-phase cardiac fibrosis and function. In the vehicle group, contractile dysfunction and left ventricle fibrosis progressed further from 4 to 8 wk after TAC but were prevented by PFD treatment beginning 4 wk after TAC. We isolated cardiac fibroblasts and vascular endothelial cells from the left ventricles of adult male mice and investigated the cell-type-specific effects of PFD. Transforming growth factor-β induced upregulated collagen 1 expression via p38 phosphorylation and downregulated claudin 5 (Cldn5) expression in cardiac fibroblasts and endothelial cells, respectively; both processes were inhibited by PFD. Moreover, PFD inhibited changes in the collagen 1 and Cldn5 expression levels, resulting in reduced fibrosis and serum albumin leakage into the interstitial space during the chronic phase in TAC hearts. In conclusion, PFD inhibited cardiac fibrosis by suppressing both collagen expression and the increased vascular permeability induced by pressure overload.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamagami
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan toruoka@cardiology.med.osaka-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
authors.forename: Takamaru
authors.initials: T
authors.lastname: Ishizu
authors.affiliation: Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
authors.forename: Keiko
authors.initials: K
authors.lastname: Miwa
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy; D006333:Heart Failure / Q000188:drug therapy*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D062507:Claudin-5; C491511:Cldn5 protein, mouse; D024042:Collagen Type I; D011728:Pyridones; C093844:pirfenidone; D048051:p38 Mitogen-Activated Protein Kinases
keywords: endothelial cells; fibroblasts; fibrosis; heart failure; tight junction