Calcium sequestration by the sarcoplasmic reticulum in heart failure.

Abstract

Time for primary review 39 days. Myocardial contraction and relaxation are dependent upon the rise and fall of cytosolic [Ca2+] in cardiac myocytes. The release and sequestration of Ca2+ by the sarcoplasmic reticulum are the principal mechanisms through which this occurs. During relaxation, Ca2+ is actively transported from the cytosol into the sarcoplasmic reticulum; during contraction, this sequestered Ca2+ is passively released into the cytosol through ryanodine-sensitive Ca2+ channels. Because of the dependence of contraction and relaxation upon ATP-dependent Ca2+ sequestration by the sarcoplasmic reticulum, the possibility that an impairment in this process contributes to the pathophysiology of heart failure has been the focus of a large body of research over the past two decades. While there seems to be a general agreement that ATP-dependent Ca2+ sequestration by the sarcoplasmic reticulum is impaired in failing human myocardium, there remains a fairly intense controversy regarding the molecular aetiology of this impairment. In this review, the rationale underlying the experimental approaches to this issue in animal models and human tissues and the conclusions that can be drawn from their results are examined. Ca2+ accumulation by cardiac sarcoplasmic reticulum occurs through the activity of SERCA2, a 105 kDa Ca2+- and Mg2+-dependent ATPase that transports Ca2+ from the cytosol to the lumen of the sarcoplasmic reticulum [1–3]. The Km of SERCA2 for Ca2+ in sarcoplasmic reticulum-enriched vesicles isolated from human left ventricular myocardium is 0.63–0.68 μM, a value which falls within the range of cytosolic Ca2+ concentrations that have been measured in intact cardiac myocytes during relaxation and contraction (0.1–1.0 μM), while the Hill coefficient is 1.6–1.7 [4, 5]. The rate of ATP-dependent Ca2+ transport by the sarcoplasmic reticulum is thus sensitive to small … * Corresponding author. Cardiology Division, 4A-100 SOM, University of Utah Health Sciences Center, 50 North Medical Drive, Salt Lake City, UT 84132, USA. Tel. (+1-801) 581 7715; Fax (+1-801) 581 7735; E-mail:matthew.movsesian@hsc.utah.edu