SPEG, an Indispensable Kinase of SERCA2a for Calcium Homeostasis

Abstract

Heart failure is one of the major causes of death worldwide. Despite the development of several treatments for heart failure, such as β-blocker, angiotensin-converting enzyme inhibitor, and mineralocorticoid receptor antagonist, most severe heart failures irreversibly progress and cannot be cured without heart transplantation. In the excitation-contraction coupling in cardiomyocytes, Ca reuptake into the sarcoendoplasmic reticulum (SR) through SERCA2a (SR Ca ATPase 2a) is a key process in the relaxation of cardiomyocytes and in the proper storage of SR Ca content for the next contraction. SERCA2a is downregulated in heart failure, and Ca reuptake to SR is reduced in diseased cardiomyocytes. As a result, excitation-contraction coupling is impaired in systolic and diastolic phases, causing a vicious spiral of SERCA2a decrement and heart failure. Hence, correcting impaired intracellular Ca homeostasis could be a therapeutic target. In heart failure animal models, overexpression of SERCA2a improved cardiac function, and gene therapy delivering the SERCA2a gene for heart failure treatment is expected to be highly successful in humans. Clinical studies, CUPID 1 and CUPID 2 (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease), have already been conducted using adeno-associated virus carrying a SERCA2a gene, but the improvement in prognosis has not been clearly shown. This inconsistency in results may be attributable to the difference in study designs and factors such as patient characteristics, virus dosage, and the gene delivery system. Thus, these factors should be adjusted in future clinical trials. Moreover, a drug that could directly affect the SERCA2a function is also expected to be developed. SERCA2a activity is finely regulated by several mechanisms, and the modulation of SERCA2a activity is critical for efficient Ca reuptake into SR. PLN (phospholamban) is highly expressed in cardiomyocytes and reversibly inhibits SERCA2a activity. Adeno-associated virus–mediated Pln knockdown rescued heart failure in an animal model. The activity and stability of SERCA2a is also regulated by post-translational modification, including the SUMO1 (small ubiquitin-related modifier 1). The level of SUMO1 is suppressed in heart failure, and Sumo1 overexpression rescued heart failure in an animal model. Those experiments lead to a better understanding of SERCA2a function; however, those findings have not yet been evaluated in humans. Further elucidation of the detailed regulatory mechanism of SERCA2a would lead to novel therapeutic concepts and contribute to drug development.