Treatment of heart failure by modulating Ca signaling protein gene expression

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Cardiac contractility is regulated by intracellular calcium concentration. Sarcoplasmic reticulum (SR) plays a major role for the regulation of intracellular calcium concentration. Ca release from SR through Ca release channel of SR induces muscle contruction, whereas Ca uptake by CaATPase of SR leads to muscle relaxation. In cardiac hypertrophy and heart failure, the expression of the Ca signaling proteins of SR have been reported to be altered. This changes in the expression of SR genes may be a cause for cardiac dysfunction and normalization of the changes in gene expression could be a novel treatment for heart failure. In this study, we attempted to elucidate a molecular mechanism for gene regulation of SR proteins, especially Ca release channel. We isolated 5'upstream region of the gene and ligated to lufiferase expression vector. We measured the luciferase activity in cardiac and skeletal muscle cells. The promotor of the gene is not tissure-specific. We found a region which suppresses the expression of the channel in skeletal muscle. This region contains E-box sequence. Gel shift assay indicated a novel bHLH protein binds to the region and regulates the expression.