SERCA2a: a prime target for modulation of cardiac contractility during heart failure

• Published in: BMB reports Vol. 46; no. 5; pp. 237 - 243
• Main Authors: Park, W.J., Gwangju Institute of Science and Technology, Gwangju, Republic of Korea, Oh, J.G., Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Society for Biochemistry and Molecular Biology 01.05.2013; 생화학분자생물학회
• Subjects: Animals; Calcium - metabolism; Calcium-Binding Proteins - metabolism; CARDIOPATHIE; Cardiovascular Agents - therapeutic use; ENFERMEDADES CARDIACAS; Gene Expression Regulation, Enzymologic; Genetic Therapy; HEART DISEASES; Heart Failure - drug therapy; Heart Failure - genetics; Humans; Inhibitor-1; Myocardial Contraction - genetics; Phospholamban; Phospholamban,Protein phosphatase,Inhibitor-1,SERCA2a; PKCα; Protein phosphatase 1; Review; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA2a; Signal Transduction; 화학
• ISSN: 1976-6696; 1976-670X
• DOI: 10.5483/BMBRep.2013.46.5.077

Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired Ca2+ cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/ endoplasmic reticulum Ca2+ATPase 2a (SERCA2a) mediates Ca2+ reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR Ca2+ uptake, are significantly reduced in failing hearts. Normalization of the SERCA2a expression level by gene delivery has been shown to restore hampered cardiac functions and ameliorate associated symptoms in pre-clinical as well as clinical studies. SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and PKCα. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation. In this review, we will highlight the molecular mechanisms underlying the regulation of SERCA2a activity and the potential therapeutic modalities for the treatment of heart failure.