Altered myocardial calcium cycling and energetics in heart failure--a rational approach for disease treatment

Abstract

Cardiomyocyte function depends on coordinated movements of calcium into and out of the cell and the proper delivery of ATP to energy-utilizing enzymes. Defects in calcium-handling proteins and abnormal energy metabolism are features of heart failure. Recent discoveries have led to gene-based therapies targeting calcium-transporting or -binding proteins, such as the cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a), leading to improvements in calcium homeostasis and excitation-contraction coupling. Here we review impaired calcium cycling and energetics in heart failure, assessing their roles from both a mutually exclusive and interdependent viewpoint, and discuss therapies that may improve the failing myocardium.

Figure 1. Excitation-contraction coupling in cardiac myocytes

During systole, an action potential depolarizes the sarcolemma and induces opening of the LTCC, allowing a minor amount of extracellular calcium to enter the cytosol (step 1). In turn, this initiates massive calcium release from the SR through the RyR2 channels (step 2). This sudden increase in cytosolic calcium concentration results in binding of calcium to TN-C and initiation of muscle contraction (step 3). The rapid removal of cytosolic calcium during diastole is primarily facilitated by SERCA2a, which returns calcium to the SR (step 4). Some calcium also exits the cell through NCX and PMCA (step 5). This decrease in intracellular calcium leads to dissociation of calcium from TN-C and muscle relaxation. Abbreviations: Na,K-ATPase, sodium-potassium ATPase; PMCA, plasma membrane calcium ATPase; NCX, sodium calcium exchanger; LTCC, voltage dependent L-type calcium channel; RyR2, ryanodine receptor isoform 2; CASQ2, calsequestrin isoform 2; HRC, histidine rich calcium binding protein; SERCA2a, sarco(endo)plasmic reticulum calcium ATPase; PLN, phospholamban; TN-C, troponin-C.

Figure 2. Structural interactions between the SR and mitochondria and energy metabolism in cardiac myocytes

The interfibrillar mitochondria and jSR are in close proximity, tethered by multiple complexes including MFN2. RyR2 and SERCA2a interactomes in the SR are responsible for calcium release and reuptake from the cytosol during muscle contraction and relaxation. These interactomes affect calcium concentration in the cytosol that is available for uptake by VDAC and MCU in the mitochondria. Changes in mitochondrial calcium concentration influence multiple processes related to energy metabolism (ATP synthesis, substrate usage). Mitochondria also produce ROS as a byproduct of energy metabolism, which affects ATP production. The energy state of the cell is defined by ATP and PCr production and consumption. Multiple proteins involved in cardiac function use ATP and their function is affected by the energetic state of the cell. Abbreviations: jSR, junctional sarcoplasmic reticulum; tSR transverse sarcoplasmic reticulum; Na,K-ATPase, sodium-potassium ATPase; PMCA, plasma membrane calcium ATPase; NCX, sodium calcium exchanger; RyR2, ryanodine receptor isoform 2; FKBP12.6, RyR2 accessory binding protein; TRI, triadin; JNC, junctin; CASQ2, calsequestrin isoform 2; HRC, Histidine rich calcium binding protein; SERCA2a, sarco(endo)plasmic reticulum calcium ATPase; PLN, phospholamban; S100A1, S100 calcium binding protein A1; TN-C, troponin-C; MFN2, mitofusin isoform 2; MCU, mitochondrial calcium uniporter; VDAC, voltage dependent anion channel; mNCX, mitochondrial sodium-calcium exchanger; CK, Creatine Kinase; PCr, phosphocreatine; Cr, creatine; ROS, reactive oxygen species.

Figure 3. Gene transfer of SERCA2a improves cardiac metabolism and energetic function in failing hearts

A. The ratio of [PCr]-to-[ATP] and the levels of both PCr and ATP are lower in failing hearts compared to healthy hearts. The overexpression of SERCA2a in failing heart restores the [PCr]-to-[ATP] ratio toward normal (del Monte et al., 2001). B. Linear relationship between the oxygen cost of calcium handling (VO₂) and left ventricular contractility (eEmax) in normal (■), failing (▲) and failing+SERCA2a (●) hearts. The slope of these linear relations represents the oxygen cost of left ventricular contractility. Treatment of failing hearts by SERCA2a gene therapy improves the energy cost of left ventricular contractility (Sakata et al., 2007).