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Sarcoplasmic reticulum proteins in heart failure
S E Lehnart1, W Schillinger, B Pieske
1Medizinische Klinik III, Universität Freiburg, Germany.
Insights
Altered calcium handling proteins, sarcoplasmic reticulum calcium ATPase (SR-Ca2+-ATPase) and sodium-calcium exchanger, are implicated in human heart failure. Their dysregulation impacts both systolic and diastolic heart function.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Altered calcium homeostasis is a key factor in human heart failure pathophysiology.
- Specific protein alterations in calcium handling pathways are suspected contributors.
Purpose of the Study:
- To analyze sarcoplasmic reticulum (SR) protein levels and sarcolemmal Na(+)-Ca2+ exchanger in failing and nonfailing human myocardium.
- To correlate these protein levels with myocardial function.
Main Methods:
- Western blot analysis was used to quantify protein levels in human heart samples.
- Protein levels were compared between failing and nonfailing hearts.
- Correlations between protein levels and functional parameters (systolic and diastolic forces) were assessed.
Main Results:
- SR calcium release channel, calsequestrin, and calreticulin levels were unchanged.
- SR-Ca(2+)-ATPase levels and its ratio to phospholamban were decreased in failing hearts.
- Na(+)-Ca2+ exchanger levels and its ratio to SR-Ca(2+)-ATPase were increased in failing hearts.
- SR-Ca(2+)-ATPase levels correlated with systolic function.
- Na(+)-Ca2+ exchanger levels correlated inversely with diastolic function.
Conclusions:
- Downregulation of SR-Ca(2+)-ATPase and upregulation of Na(+)-Ca2+ exchanger contribute to impaired systolic and diastolic function in human heart failure.
- These specific protein alterations are significant in the pathophysiology of heart failure.
Abstract:
Altered calcium homeostasis may play a key role in the pathophysiology of human heart failure. Levels of sarcoplasmic reticulum (SR) proteins and sarcolemmal Na(+)-Ca2+ exchanger were analyzed by Western blot in failing and nonfailing human myocardium and related to myocardial function. Levels of the SR calcium release channel and of calcium storage proteins (calsequestrin and calreticulin) were not different in nonfailing and failing hearts. However, proteins involved in calcium removal were significantly altered in the failing human heart: (1) SR-Ca(2+)-ATPase levels and the ratio of SR-Ca(2+)-ATPase to its inhibitory protein phospholamban were significantly decreased, and (2) Na(+)-Ca2+ exchanger levels and the ratio of Na(+)-Ca2+ exchanger to SR-Ca(2+)-ATPase were significantly increased. SR-Ca(2+)-ATPase levels were closely correlated to systolic function as evaluated by frequency potentiation of contractile force. The frequency-dependent rise of diastolic force was inversely correlated with protein levels of Na(+)-Ca2+ exchanger. These findings indicate that altered expression of SR-Ca(2+)-ATPase and Na(+)-Ca2+ exchanger is relevant for altered systolic and diastolic function in human heart failure.