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JACC Basic Transl Sci. 2019 Apr 29;4(2):188-199. doi: 10.1016/j.jacbts.2018.11.007. eCollection 2019 Apr.

Phosphorylation of Hsp20 Promotes Fibrotic Remodeling and Heart Failure.

Author information

1
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
2
Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
3
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
4
Molecular Biology Division, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

Abstract

Cardiomyocyte-specific increases in phosphorylated Hsp20 (S16D-Hsp20) to levels similar to those observed in human failing hearts are associated with early fibrotic remodeling and depressed left ventricular function, symptoms which progress to heart failure and early death. The underlying mechanisms appear to involve translocation of phosphorylated Hsp20 to the nucleus and upregulation of interleukin (IL)-6, which subsequently activates cardiac fibroblasts in a paracrine fashion through transcription factor STAT3 signaling. Accordingly, treatment of S16D-Hsp20 mice with a rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) attenuated interstitial fibrosis and preserved cardiac function. These findings suggest that phosphorylated Hsp20 may be a potential therapeutic target in heart failure.

KEYWORDS:

Ccl2, C-C motif chemokine ligand 2; Ccl3, C-C motif chemokine ligand 3; Col1a1, collagen 1A1; Col3A1, collagen 3A1; ECM, extra-cellular matrix; Hsp, heat shock protein; Hsp20; I/R, ischemia/reperfusion; IL, interleukin; IL-6; Postn, periostin; SMA, smooth muscle actin; STAT3, signal transducer and activator of transcription 3; TG, transgenic; TGF, transforming growth factor; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WT, wild type; fibroblast; heart failure; remodeling

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