CALCIUM HANDLING PROTEINS IN THE FAILING HUMAN HEART

There is accumulating evidence that disturbed calcium homeostasis may play a key role in the pathophysiology of human heart failure. Because disturbed calcium handling could result from altered protein expressi on, levels of calcium handling proteins were quantitated by Western Bl ot analysis in failing and nonfailing human myocardium from hearts wit h endstage failing dilated or ischemic cardiomyopathy. Protein levels of the sarcoplasmic reticulum calcium release channel (ryanodine recep tor) and of calcium storage proteins (calsequestrin and calreticulin) were similar in failing and nonfailing human myocardium. However, prot eins involved in calcium removal from the cytosol were significantly a ltered in the failing human heart: 1) SR-Ca2+-ATPase, relevant for rem oval of calcium from the cytosol into the lumen of the sarcoplasmic re ticulum, was decreased; 2) phospholamban, which inhibits the SR-Ca2+-A TPase in the basal unphosphorylated state, was slightly decreased; 3) the ratio of SR-Ca2+-ATPase to phospholamban was decreased; 4) the sar colemmal Na+-Ca2+-exchanger, relevant for trans-sarcolemmal calcium ex trusion was increased in the failing hearts. In summary, altered level s of proteins involved in calcium removal from the cytosol suggest an increase in transsarcolemmal calcium elimination relative to sarcoplas mic reticulum calcium removal. These findings support the concept that reduced function of the sarcoplasmic reticulum to accumulate calcium may reflect a major defect in excitation-contraction coupling in human heart failure.