Abstract 334: An Inotropic S100A1-derived Peptide Enhances Contractile Performance and Survival of Post-ischemic Failing Hearts

Abstract

S100A1 gene therapy was suggested as therapeutic for cardiomyopathies since myocardial levels of S100A1 are decreased in heart failure. S100A1 increases systolic and diastolic performance of cardiomyocytes through enhanced Ca2+-induced SR Ca2+ release and augmented SR Ca2+ re-uptake. These effects are due to enhanced systolic Type 2 Ryanodine Receptor (RyR2) and diastolic Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a) activity. The S100A1 C-terminus (S100A1ct) was recently shown to be the bioactive domain of the protein. The aim of this study was therefore to characterize the effects of an S100A1ct-derived peptide on cardiomyocyte function and to test its therapeutic action in a mouse model of heart failure. An S100A1ct-derived peptide encompassing aa75-85 of the human S100A1 protein and preceded by a hydrophilic motif (DKDDPP) was named S100A1ct6/11. S100A1ct6/11 was cell permeable and accumulated in the intracellular space of intact rat ventricular cardiomyocytes in a striated pattern, similar to endogenous S100A1. S100A1ct6/11 exerted a time- and dose-dependent positive inotropic effect in electrical field stimulated rat ventricular cardiomyocytes. This effect was associated with the regulation of the SR calcium content. Peptides encompassing aa75-85 derived from S100 paralogs A4 and B did not mimic S100A1ct6/11-mediated inotropy. S100A1ct6/11 protected cardiomyocytes from pro-arrythmic store overload-induced calcium leak as well as from chronic caffeine exposure-induced apoptotic cell death. Mice intravenously injected with S100A1ct6/11 exhibited a significant enhancement of LV contractile performance under basal and βAR-stimulated conditions. Daily intraperitoneal administration of S100A1ct6/11 for two weeks to mice with post-ischemic contractile dysfunction resulted in significantly improved contractile performance and survival due to reduced myocardial apoptosis. Moreover, this treatment protected failing hearts with caffeine-induced leaky RyR2 channels from βAR-triggered lethal ventricular tachyarrhythmias. In conclusion, administration of the S100A1ct6/11 peptide may represent a novel option for the treatment of cardiomyopathies without apparent side effects.