S100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models
Abstract
BACKGROUND: The EF-hand Ca 2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca 2+ ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75–94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts. METHODS: We applied an integrative translational research pipeline ranging from in silico computational molecular modeling and in vitro biochemical molecular assays as well as isolated rodent and human cardiomyocyte performance assessments to in vivo safety and efficacy studies in small and large animal cardiac disease models. RESULTS: We characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in preclinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca 2+ cycling and prevents β-adrenergic receptor–triggered Ca 2+ imbalances by targeting SERCA2a and RyR2 activity. In line with the S100A1ct-mediated enhancement of SERCA2a activity, modeling suggests an interaction of the peptide with the transmembrane segments of the sarcoplasmic Ca 2+ pump. Incorporation of a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo. CONCLUSIONS: S100A1ct is a promising lead for the development of novel peptide-based therapeutics against heart failure with reduced ejection fraction.
Article Details
Authors (23)
Dorothea Kehr
Division of Molecular and Translational Cardiology (D.Z., M.B., S.G., H.W., A.K.S., D.K., M.Q., A.J., J.R., P.M.), University Hospital Heidelberg, Germany.
Julia Ritterhoff
Division of Molecular and Translational Cardiology (D.Z., M.B., S.G., H.W., A.K.S., D.K., M.Q., A.J., J.R., P.M.), University Hospital Heidelberg, Germany.
Manuel Glaser
Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.).
Lukas Jarosch
Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.).
Rafael E. Salazar
Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.).
Kristin Spaich
Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany.
Karl Varadi
Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany.
Jennifer Birkenstock
Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany.
Michael Egger
Molecular and Translational Cardiology (D.K., J.R., K.S., K.V., J.B., M.E., A.J., M.B., P.M.), Heidelberg University Hospital (UKHD), Germany.
Erhe Gao
Center for Translational Medicine, Temple University, Philadelphia, PA (E.G.).
Walter J. Koch
Division of Cardiovascular and Thoracic Surgery, Duke University, Durham, NC (W.J.K.).
Max Sauter
Department of Clinical Pharmacology and Pharmacoepidemiology (M.S.), Heidelberg University Hospital (UKHD), Germany.
Marc Freichel
Department of General Pharmacology, Pharmakologisches Institut, Universität Heidelberg
Hugo A. Katus
Deutsches Zentrum für Herz- und Kreislaufforschung, Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.B., E.M., A.K.S., S.M., D.K., M.Q., M.V., V.K., J.W., P.S., C.D., H.A.K., N.F., J.R., P.M.).
Norbert Frey
Andreas Jungmann
Division of Molecular and Translational Cardiology (D.Z., M.B., S.G., H.W., A.K.S., D.K., M.Q., A.J., J.R., P.M.), University Hospital Heidelberg, Germany.
Cornelius Busch
Department of Anesthesiology (C.B.), Heidelberg University Hospital (UKHD), Germany.
Paul J. Mather
Perelman School of Medicine, University of Pennsylvania, Philadelphia (P.J.M.).
Arjang Ruhparwar
Division for Cardiothoracic-, Transplantation- and Vascular Surgery, Hannover Medical School, Hannover, Germany (A.R.).
Martin Busch
Mirko Völkers
Rebecca C. Wade
Heidelberg Institute for Theoretical Studies (HITS), Germany (M.G., L.J., R.E.S., R.C.W.).
Patrick Most