Targeting sarcoplasmic reticulum calcium handling proteins as therapy for cardiac disease (original) (raw)

Hellenic journal of cardiology : HJC = Hellēnikē kardiologikē epitheōrēsē

arcoplasmic reticulum (SR) calcium (Ca 2+) uptake and its subsequent release regulate excitation-contraction coupling of the heart. In cardiac cells (Figure 1), the SR serves as a reservoir from which Ca 2+ is released into the cytosol via the ryanodine receptor and its associated proteins, initiating contraction of the heart. 1 Sequestration of Ca 2+ from the cytosol into the SR lumen, and thus relaxation of the heart, is mediated by the SR Ca ATP-ase (SERCA) and its regulatory protein, phospholamban (PLN). 2 Several kinases and phosphatases regulate excitation-contraction coupling in the heart by altering the phosphorylation state of key Ca 2+ handling proteins. Disturbed excitation-contraction coupling, in particular altered intracellular Ca 2+ cycling, may underlie contractile dysfunction in human and animal models of heart failure. 3-6 Heart failure is a major public health problem that affects nearly five million Americans, necessitates one million costly hospitalizations each year, and remains the leading cause of mortality and morbidity in developed nations. 7,8 Several lines of evidence report that much of the contractile deficit in human heart failure is due to diminished peak systolic Ca 2+ transients, increased diastolic intracellular Ca 2+ concentrations, and prolonged diastolic decay of myocyte Ca 2+ transients (Figure 1B). A central factor limiting systolic Ca 2+ transient amplitude is decreased SR Ca 2+ content. Several studies reported a diminished SR Ca 2+ content in heart failure, 9 and the fraction of SR Ca 2+ released upon contraction is strongly influenced by the SR Ca 2+ load. 10-14 Currently, there are two debated causes of SR Ca 2+ depletion: (1) decreased SERCA Ca 2+ uptake and/or an increased activity of the Na +-Ca 2+ exchanger; and (2) increased SR Ca 2+ leak from the ryanodine receptor. There is an ongoing controversy over the contribution of each of these factors to unloading of the SR. However the relative contributions of each may vary among heart failure models and disease stages, 9,15 and it is likely that the molecular basis of heart failure may involve a combination of depressed SR Ca 2+ uptake and enhanced SR Ca 2+ leak. 16 Indeed, elucidating the mechanism(s) responsible for impaired Ca 2+ cycling in the failing heart is quite challenging, as there are many proteins involved. Alterations in expression levels, function, localization, and/or regulation of any one or a combination of these proteins may disturb intracellular Ca 2+ homeostasis, leading to the development of heart failure. In this review, we will highlight the critical role of SR Ca 2+ cycling proteins, SERCA, PLN, ryanodine receptor, calsequestrin, triadin, junctin, and the histidine-rich calcium binding protein (HRC), in the heart. We will also summarize studies of heart failure in human and animal models that have indicated that decreased SR Ca 2+ uptake, alterations in SR Ca 2+ storage, and abnormal SR Ca 2+ re-132 ñ HJC (Hellenic Journal of Cardiology)