Author + information
- Received August 22, 2018
- Revision received September 27, 2018
- Accepted November 14, 2018
- Published online April 29, 2019.
- George T. Gardner, PhDa,
- Joshua G. Travers, PhDb,
- Jiang Qian, PhDa,
- Guan-Sheng Liu, PhDa,
- Kobra Haghighi, PhDa,
- Nathan Robbins, MSc,
- Min Jiang, BSc,
- Yutian Li, MSa,
- Guo-Chang Fan, PhDa,
- Jack Rubinstein, MDc,
- Burns C. Blaxall, PhDb and
- Evangelia G. Kranias, PhDa,d,∗ ()
- aDepartment of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
- bDepartment of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- cDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
- dMolecular Biology Division, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- ↵∗Address for correspondence:
Dr. Evangelia G. Kranias, Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0575.
• PKA-phosphorylation of Hsp20 is elevated in human failing hearts.
• Increases in phosphorylated Hsp20 in vivo are associated with fibrotic remodeling and reduced left ventricular function.
• The phosphorylated Hsp20 in cardiomyocyte promotes upregulation of IL-6 and its subsequent paracrine actions on the cardiac fibroblast.
• Blockade of IL-6 effects ex vivo and in vivo reduces the pro-fibrotic effects of phosphorylated Hsp20.
• Targeting phosphorylated Hsp20 in the cardiomyocyte may represent a potential therapeutic strategy to mitigate fibrotic remodeling and preserve function in the failing heart.
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.
This research was supported by U.S. National Institutes of Health (NIH) grants R01 HL26057, R01 HL64018 (EGK), R01 HL132551, R01 HL133695, R01 HL134321 to Dr. Blaxall; and predoctoral fellowship grants 15PRE25090055 and NIH grant T32 HL125204 from the American Heart Association Great Rivers Affiliate to Dr. Gardner. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and U.S. Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 22, 2018.
- Revision received September 27, 2018.
- Accepted November 14, 2018.
- 2019 The Authors