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

Abstract

Heart failure is one of the leading causes of sudden death indeveloped countries. While current therapies are mostly aimedat mitigating associated symptoms, novel therapies targetingthe subcellular mechanisms underlying heart failure areemerging. Failing hearts are characterized by reduced contractileproperties caused by impaired Ca2+ cycling between thesarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2a (SERCA2a) mediatesCa2+ reuptake into the SR in cardiomyocytes. Of note, theexpression level and/or activity of SERCA2a, translating to thequantity of SR Ca2+ uptake, are significantly reduced in failinghearts. Normalization of the SERCA2a expression level bygene delivery has been shown to restore hampered cardiacfunctions and ameliorate associated symptoms in pre-clinicalas well as clinical studies. SERCA2a activity can be regulated atmultiple levels of a signaling cascade comprised of phospholamban,protein phosphatase 1, inhibitor-1, and PKCα.SERCA2 activity is also regulated by post-translational modificationsincluding SUMOylation and acetylation. In this review,we will highlight the molecular mechanisms underlying theregulation of SERCA2a activity and the potential therapeuticmodalities for the treatment of heart failure. [BMB Reports2013; 46(5): 237-243]

Keywords

• Inhibitor-1
• Phospholamban
• PKCα
• Protein phosphatase 1
• SERCA2a