S100A1: A regulator of myocardial contractility

doi:10.1073/pnas.241393598

S100A1: A regulator of myocardial contractility

^*Medizinische Klinik II, Medizinische Universität zu Lübeck, 23538 Lübeck, Germany; ^†Abteilung Innere Medizin III, Medizinische Universität Heidelberg, 69115 Heidelberg, Germany; ^‡Abteilung Kardiologie und Pneumologie, Zentrum Innere Medizin, Universität Göttingen, 37075 Göttingen, Germany; ^§Johns Hopkins School of Medicine, Division of Cardiology, Baltimore, MD 21205; ^¶Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen, 91054 Erlangen, Germany; ^‖Max Delbrück Zentrum, Berlin-Buch, 13125 Berlin, Germany; ^**Institute of Biomedical Life Science, University of Glasgow, G128QQ Glasgow, Scotland; and ^‡‡Department of Surgery, Duke University Medical Center, Durham, NC 27710

Edited by Eugene Braunwald, Partners HealthCare System, Inc., Boston, MA, and approved September 24, 2001 (received for review July 27, 2001)

Abstract

S100A1, a Ca²⁺ binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been found to colocalize with the sarcoplasmic reticulum (SR) and the contractile filaments in cardiac tissue. Because S100A1 is known to modulate SR Ca²⁺ handling in skeletal muscle, we sought to investigate the specific role of S100A1 in the regulation of myocardial contractility. To address this issue, we investigated contractile properties of adult cardiomyocytes as well as of engineered heart tissue after S100A1 adenoviral gene transfer. S100A1 gene transfer resulted in a significant increase of unloaded shortening and isometric contraction in isolated cardiomyocytes and engineered heart tissues, respectively. Analysis of intracellular Ca²⁺ cycling in S100A1-overexpressing cardiomyocytes revealed a significant increase in cytosolic Ca²⁺ transients, whereas in functional studies on saponin-permeabilized adult cardiomyocytes, the addition of S100A1 protein significantly enhanced SR Ca²⁺ uptake. Moreover, in Triton-skinned ventricular trabeculae, S100A1 protein significantly decreased myofibrillar Ca²⁺ sensitivity ([EC_50%]) and Ca²⁺ cooperativity, whereas maximal isometric force remained unchanged. Our data suggest that S100A1 effects are cAMP independent because cellular cAMP levels and protein kinase A-dependent phosphorylation of phospholamban were not altered, and carbachol failed to suppress S100A1 actions. These results show that S100A1 overexpression enhances cardiac contractile performance and establish the concept of S100A1 as a regulator of myocardial contractility. S100A1 thus improves cardiac contractile performance both by regulating SR Ca²⁺ handling and myofibrillar Ca²⁺ responsiveness.

Footnotes

↵ †† To whom reprint requests should be addressed. E-mail: remppis{at}medinf.mu-luebeck.de.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

SR,

sarcoplasmic reticulum;

EHT,

engineered heart tissue;

GFP,

green fluorescent protein;

WT,

wild type;

PLB,

phospholamban;

CSQ,

calsequestrin;

SERCA,

sarcoplasmic reticulum Ca2+ ATPase