Sarcoplasmic reticulum Ca-ATPase–phospholamban interactions and dilated cardiomyopathy

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Abstract

Dilated cardiomyopathy is a disease of the heart muscle resulting from a diverse array of conditions that damages the heart and impairs myocardial function. Heart failure occurs when the heart is unable to pump blood at a rate which can accommodate the heart muscle’s metabolic requirements. Several signaling pathways have been shown to be involved in the induction of cardiac disease and heart failure. Many of these pathways are linked to cardiac sarcoplasmic reticulum (SR) Ca cycling directly or indirectly. A large body of evidence points to the central role of abnormal Ca handling by SR proteins, Ca-ATPase pump (SERCA2a) and phospholamban (PLN), in pathophysiological heart conditions, compromising the contractile state of the cardiomyocytes. This review summarizes studies which highlight the key role of these two SR proteins in the regulation of cardiac function, the significance of SERCA2a–PLN interactions using transgenic approaches, and the recent discoveries of human PLN mutations leading to disease states. Finally, we will discuss extrapolation of experimental paradigms generated in animal models to the human condition.

Section snippets

SR calcium cycling proteins and cardiac function

The SR is an intracellular membranous network which plays an essential role in mediating contraction and relaxation in the adult cardiomyocyte. During contraction, the SR serves as a reservoir from which Ca is released into the cytosol via the ryanodine receptor. Sequestration of Ca from the cytosol into the SR lumen and, thus, relaxation of the heart is mediated by the sarcoplasmic reticulum Ca-ATPase pump and its regulatory protein, phospholamban (Fig. 1A).

The sarcoplasmic reticulum Ca-ATPase

SR Ca handling in the failing heart

Heart failure is a low cardiac output disease characterized by circulatory congestion and both systolic and diastolic dysfunction. However, the critical early events that impair myocyte performance remain to be elucidated. Hallmarks of cardiac failure include marked ventricular hypertrophy or dilation, decreased velocity of contraction, decreased rates of relaxation, and pathological remodeling of the heart. Several signaling pathways have been shown to be involved in the induction of

SERCA2a–PLN interactions and cardiac function

As described earlier, PLN and SERCA2a proteins are major regulators of the SR Ca transport, and alterations in the basal levels of either protein could have profound effects by changing the equilibrium of the PLN/SERCA2a ratio and consequently altering intracellular Ca homeostasis. Thus, a cross-talk must exist between these two proteins in order to maintain Ca homeostasis in normal and pathologic conditions, although there is no clear evidence if the expression of one protein dictates the

SERCA2a and PLN as therapeutic targets for heart failure

Since it has been suggested that the PLN/SERCA2a ratio and the degree of PLN inhibition of SERCA2a are important determinants of depressed SR function and altered Ca cycling in the failing human myocardium, attractive therapeutic targets for heart failure have been SERCA2a and PLN. Indeed, SERCA2a overexpression and PLN inhibition have been remarkably successful in improving myocardial function of a variety of experimental heart failure models.

Studies have demonstrated that gene transfer of

Phospholamban mutations

In human disease and experimental animal models, depressed Ca handling in failing cardiomyocytes is widely attributed to impaired SR function, suggesting a causal role for altered calcium cycling in the development or progression of heart failure. In mice, disruption of the gene encoding PLN or expression of dominant negative PLN mutants enhances SR and cardiac function; however, until recently, effects of PLN mutations in humans were unknown. In recent years, the genetic basis for human

From mouse to humans: limitations and cautionary extrapolations

In light of the data that interference with the PLN–SERCA2a interaction may be detrimental in humans, although demonstrated to be beneficial in animal models, it is essential to consider the profound differences between animal models and the human condition. Most obvious is that animal models and humans differ for reasons such as overall size, life span, circulatory physiology, and pharmacological responses to stimulation. The discrepancy between the cardiac phenotypes of PLN ablation in mice

Conclusion

Convincing evidence suggests that the impaired function of the SR to cycle Ca during diastole and systole is a critical defect in cardiomyocytes from failing hearts. Diminished contractile function may promote hypertrophy, leading to chronically depressed contractile function, pathological remodeling, and ultimately reduced cardiac output and heart failure. Strategies to interfere with the PLN/SERCA2a interaction have been proposed as therapy to improve Ca cycling, contractility, and relaxation

Acknowledgment

This research was supported by NIH Grants HL-26057, HL-64018, and HL-52318 to E.G.K.

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