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Calcium handling proteins in the failing human heart
G Hasenfuss1, M Meyer, W Schillinger
1Medizinische Klinik III, Universität Freiburg, Germany.
Insights
Disturbed calcium handling in heart failure is linked to altered protein levels. Specifically, proteins removing calcium from the cytosol are changed, impacting heart muscle contraction.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Disturbed calcium homeostasis is implicated in human heart failure pathophysiology.
- Altered protein expression may underlie impaired calcium handling in heart failure.
Purpose of the Study:
- To quantitate levels of calcium handling proteins in failing and nonfailing human myocardium.
- To investigate the role of protein alterations in the pathophysiology of human heart failure.
Main Methods:
- Western Blot analysis was used to measure protein levels.
- Samples were obtained from failing (dilated or ischemic cardiomyopathy) and nonfailing human hearts.
Main Results:
- Sarcoplasmic reticulum calcium release channel and storage protein levels were similar between failing and nonfailing hearts.
- Proteins involved in cytosolic calcium removal were altered: SR-Ca(2+)-ATPase and phospholamban decreased, while the sarcolemmal Na(+)-Ca(2+)-exchanger increased.
- The ratio of SR-Ca(2+)-ATPase to phospholamban was decreased in failing hearts.
Conclusions:
- Altered protein levels suggest increased transsarcolemmal calcium elimination relative to sarcoplasmic reticulum calcium removal in heart failure.
- Reduced sarcoplasmic reticulum calcium uptake may represent a significant defect in excitation-contraction coupling in human heart failure.
Abstract:
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 expression, levels of calcium handling proteins were quantitated by Western Blot analysis in failing and nonfailing human myocardium from hearts with endstage failing dilated or ischemic cardiomyopathy. Protein levels of the sarcoplasmic reticulum calcium release channel (ryanodine receptor) and of calcium storage proteins (calsequestrin and calreticulin) were similar in failing and nonfailing human myocardium. However, proteins involved in calcium removal from the cytosol were significantly altered in the failing human heart: 1) SR-Ca(2+)-ATPase, relevant for removal of calcium from the cytosol into the lumen of the sarcoplasmic reticulum, was decreased; 2) phospholamban, which inhibits the SR-Ca(2+)-ATPase in the basal unphosphorylated state, was slightly decreased; 3) the ratio of SR-Ca(2+)-ATPase to phospholamban was decreased; 4) the sarcolemmal Na(+)-Ca(2+)-exchanger, relevant for transsarcolemmal calcium extrusion was increased in the failing hearts. In summary, altered levels of proteins involved in calcium removal from the cytosol suggest an increase in transsarcolemmal calcium elimination relative to sarcoplasmic 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.