title: SERCA2a: a prime target for modulation of cardiac contractility during heart failure.
abstract: 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 Ca(2+) cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/ endoplasmic reticulum Ca(2+)ATPase 2a (SERCA2a) mediates Ca(2+) reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR Ca(2+) 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.
authors.affiliation: Global Research Laboratory and College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea. woojinpark@me.com
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002317:Cardiovascular Agents / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D009200:Myocardial Contraction / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D002317:Cardiovascular Agents; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban