S100A1: A regulator of myocardial contractility

S100A1, a Ca2+ binding protein of the EF-hand type, is preferentially expre ssed in myocardial tissue and has been found to colocalize with the sarcopl asmic reticulum (SR) and the contractile filaments in cardiac tissue. Becau se S100A1 is known to modulate SR Ca2+ handling in skeletal muscle, we soug ht to investigate the specific role of S100A1 in the regulation of myocardi al contractility. To address this issue, we investigated contractile proper ties of adult cardiomyocytes as well as of engineered heart tissue after S1 00A1 adenoviral gene transfer. S100A1 gene transfer resulted in a significa nt increase of unloaded shortening and isometric contraction in isolated ca rdiomyocytes and engineered heart tissues, respectively. Analysis of intrac ellular Ca2+ cycling in S100A1-over-expressing cardiomyocytes revealed a si gnificant increase in cytosolic Ca2+ transients, whereas in functional stud ies on saponin-permeabilized adult cardiomyocytes, the addition of S100A1 p rotein significantly enhanced SR Ca2+ uptake. Moreover, in Triton-skinned v entricular trabeculae, S100A1 protein significantly decreased myofibrillar Ca2+ sensitivity ([EC50%]) and Ca2+ cooperativity, whereas maximal isometri c force remained unchanged. Our data suggest that S100A1 effects are cAMP i ndependent because cellular cAMP levels and protein kinase A-dependent phos phorylation of phospholamban were not altered, and carbachol failed to supp ress S100A1 actions. These results show that S100A1 overexpression enhances cardiac contractile performance and establish the concept of S100A1 as a r egulator of myocardial contractility. S100A1 thus improves cardiac contract ile performance both by regulating SIR Ca2+ handling and myofibrillar Ca2responsiveness.