Calcium cycling proteins and heart failure: mechanisms and therapeutics

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Abstract

Ca²⁺-dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca²⁺ cycling refers to the release and reuptake of intracellular Ca²⁺ that drives muscle contraction and relaxation. In failing hearts, Ca²⁺ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca²⁺ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca²⁺ storage organelle in muscle. Defects in the regulation of Ca²⁺ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/Ca²⁺ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in “leaky” channels in failing hearts. These leaky RyR2s contribute to depletion of Ca²⁺ from the SR, and the leaking Ca²⁺ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca²⁺ reuptake that conspires with leaky RyR2 to deplete SR Ca²⁺. Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca²⁺-release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca²⁺ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca²⁺ cycling in the heart.

Authors

Andrew R. Marks