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Phospholamban: a promising therapeutic target in heart failure?
A G Schmidt1, I Edes, E G Kranias
1Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, OH 45267, USA.
Insights
Altering phospholamban and SR Ca2+ ATPase interaction may treat heart failure. Phospholamban deficiency in animal models prevented dilated cardiomyopathy and heart failure progression.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Dilated cardiomyopathy and heart failure involve altered cardiac function and remodeling.
- Defects in cardiac excitation-contraction coupling, particularly sarcoplasmic reticulum (SR) Ca2+ handling, are implicated.
- SR Ca2+ ATPase and its regulator phospholamban are key players in myocardial contractility.
Purpose of the Study:
- To review the role of phospholamban and SR Ca2+ ATPase in heart failure.
- To explore phospholamban/SR Ca2+ ATPase as potential therapeutic targets.
- To discuss the clinical relevance of SR dysfunction in heart failure.
Main Methods:
- Summarizing structural and genetic studies on phospholamban's physiological role.
- Analyzing clinical data on phospholamban/SR Ca2+ ATPase in human heart failure.
- Reviewing evidence from genetically engineered mouse models of SR dysfunction.
Main Results:
- Phospholamban is a principal regulator of cardiac contractility and beta-adrenergic stimulation.
- A phospholamban/SR Ca2+ ATPase imbalance is observed in human heart failure.
- SR dysfunction contributes to heart failure onset and progression in mouse models.
- Phospholamban deficiency may protect against dilated cardiomyopathy and heart failure progression.
Conclusions:
- SR Ca2+ ATPase and phospholamban are critical for cardiac function.
- Therapeutic strategies targeting the phospholamban/SR Ca2+ ATPase interaction show promise for heart failure treatment.
- Understanding SR dysfunction is crucial for developing novel heart failure therapies.
Abstract:
Dilated cardiomyopathy and end-stage heart failure result in characteristic functional, biochemical and molecular alterations. Multiple defects in cardiac excitation-contraction coupling have been suggested to underlie disturbed myocardial function and progressive remodeling. Ca2+ uptake and release by the sarcoplasmic reticulum (SR) have been shown to be altered in various animal models and human conditions. This review will focus on SR Ca2+ ATPase and its regulatory protein, phospholamban, as potential therapeutic targets. We summarize structural and genetic approaches, which have helped to elucidate the physiological role of phospholamban as a principal regulator of cardiac contractility and beta-adrenergic stimulation in the heart. These findings are extended to the clinical arena, indicating a phospholamban/SR Ca2+ ATPase mismatch in human heart failure. Evidence is then provided, using genetically engineered mouse models, that SR dysfunction may play a key role in the onset and progression of heart failure. Phospholamban deficiency may prevent such left ventricular dysfunction and its progression to heart failure in some of the animal models with dilated cardiomyopathy. Based on these findings, we discuss the question of whether and how interfering with the phospholamban/SR Ca2+ ATPase interaction may be a promising therapeutic approach for heart failure.