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Am J Physiol Heart Circ Physiol. 2015 Aug 1;309(3):H512-22. doi: 10.1152/ajpheart.00137.2015. Epub 2015 Jun 8.

Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts.

Author information

1
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
2
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.
3
Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
4
Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
5
Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.

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.

KEYWORDS:

endothelial cells; fibroblasts; fibrosis; heart failure; tight junction

PMID:
26055790
DOI:
10.1152/ajpheart.00137.2015
[Indexed for MEDLINE]
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