Biochemical and Biophysical Research Communications
Sarcoplasmic reticulum Ca-ATPase–phospholamban interactions and dilated cardiomyopathy
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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2017, Biochimica et Biophysica Acta - Molecular Basis of DiseaseGenetic basis of dilated cardiomyopathy
2016, International Journal of CardiologyPhospholamban and sarcolipin: Are they functionally redundant or distinct regulators of the Sarco(Endo)Plasmic Reticulum Calcium ATPase?
2016, Journal of Molecular and Cellular CardiologyCitation Excerpt :It was first identified as a phosphoprotein by Tada et al., in 1975 [32,33]. Extensive work done in the MacLennan, Jones and Kranias laboratories has clearly demonstrated the regulation of SERCA by PLB [5,7,10,17,34–50]. They showed that active PLB is a monomer and can easily associate into pentamers [43,51–54].
Ellagic acid and gingerol, activators of the sarco-endoplasmic reticulum Ca<sup>2+</sup>-ATPase, ameliorate diabetes mellitus-induced diastolic dysfunction in isolated murine ventricular myocardia
2013, European Journal of PharmacologyCitation Excerpt :An observation consistent with this view is that an increase in myocardial SERCA type 2a protein level with transgenic technology in streptozotocin-induced diabetic mice improved myocardial diastolic function (Suarez et al., 2008; Trost et al., 2002). Impaired SR function and decreased SERCA levels are not unique to diabetic cardiomyopathy, but were also observed in end-stage heart failure due to ischemic, dilated and hypertrophic cardiomyopathy (Haghighi et al., 2004; Schotten et al., 1999), and in aging hearts (Jiao et al., 2012). This implies that SERCA activators might be of therapeutic benefit under these conditions.