Abstract 14967: PKA-Phosphorylation of Hsp20 is Associated With Detrimental Cardiac Remodeling and Early Death
Introduction: Heat shock protein 20 (Hsp20) enhances cardiac contractility through inhibition of protein phosphatase 1 (PP1) and elicits protection under stress conditions. Hsp20 is also the only small heat shock protein that is phosphorylated by protein kinase A (PKA) at Ser16. Interestingly, phosphorylation of Hsp20 is highly elevated following ischemia/reperfusion injury and in heart failure (HF), but the significance of this phosphorylation remains unclear.
Results: Acute increases in the levels of constitutively phosphorylated Hsp20 (S16D-Hsp20) in adult rat cardiomyocytes enhanced protection from apoptosis and increased contractility to a greater extent than WT-Hsp20. These findings suggested that hyper-phosphorylation of Hsp20 may have beneficial effects. To test this hypothesis in vivo, we generated a mouse model with cardiac-specific overexpression of S16D-Hsp20 and characterized a line, expressing similar levels of phosphorylated Hsp20, as those observed in human HF. In contrast to the findings with acute overexpression, transgenic mice exhibited early death with 50% dead by 6 months of age. Examination of function at 3 months indicated decreased PP1 activity, hyper-phosphorylation of phospholamban and increased cardiomyocyte contractility. However, cardiac remodeling was present and this was observed as early as 2 months of age, associated with increased left ventricular end-diastolic volume and interstitial as well as perivascular fibrosis. The underlying mechanism appears to involve a novel interaction of Hsp20 with Toll-like receptor-4, which was enhanced by S16D-Hsp20 and drove activation of the immune response, accompanied by increased expression of pro-inflammatory cytokines IL-6 and MCP1. These findings indicate that long term increases in cardiac Hsp20 phosphorylation may impair function and promote pathological remodeling.
Conclusions: Phosphorylation of Hsp20 under stress conditions may represent an initial compensatory response in the heart that becomes maladaptive over time and contributes to remodeling and depressed function. Thus, the observed increases in phosphorylated Hsp20 in failing hearts may constitute an additional insult to the already compromised heart.
Author Disclosures: G. Gardner: None. G. Liu: None. J. Qian: None. M. Jiang: None. W. Cai: None. M. Tranter: None. G. Fan: None. J. Rubinstein: None. E. Kranias: None.
- © 2016 by American Heart Association, Inc.