title: Extracellular S100A1 protein inhibits apoptosis in ventricular cardiomyocytes via activation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2).
abstract: S100A1 is a Ca2+-binding protein of the EF-hand type that belongs to the S100 protein family. It is specifically expressed in the myocardium at high levels and is considered to be an important regulator of cardiac contractility. Because the S100A1 protein is released into the extracellular space during ischemic myocardial injury, we examined the cardioprotective potential of the extracellular S100A1 protein on ventricular cardiomyocytes in vitro. In this report we show that extracellularly added S100A1 protein is endocytosed into the endosomal compartment of neonatal ventricular cardiomyocytes via a Ca2+-dependent clathrin-mediated process. S100A1 uptake protects neonatal ventricular cardiomyocytes from 2-deoxyglucose and oxidative stress-induced apoptosis in vitro. S100A1-mediated anti-apoptotic effects involve specific activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pro-survival pathway, including activation of phospholipase C, protein kinase C, mitogen-activated protein kinase kinase 1, and ERK1/2. In contrast, neither transsarcolemmal Ca2+ influx via the L-type channel nor protein kinase A activity seems to take part in the S100A1-mediated signaling pathway. In conclusion, this study provides evidence for the S100A1 protein serving as a novel cardioprotective factor in vitro. These findings warrant speculation that injury-dependent release of the S100A1 protein from cardiomyocytes may serve as an intrinsic mechanism to promote survival of the myocardium in vivo.
authors.affiliation: Innere Medizin III, Universität Heidelberg, 69115 Heidelberg, Germany. patrick.most@med.uni-heidelberg.de
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.forename: Carmen
authors.initials: C
authors.lastname: Eicher
authors.forename: Christopher
authors.initials: C
authors.lastname: Schweda
authors.forename: Philipp
authors.initials: P
authors.lastname: Ehlermann
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Eva
authors.initials: E
authors.lastname: Loeffler
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Cora-Ann
authors.initials: CA
authors.lastname: Schoenenberger
authors.forename: Andrew
authors.initials: A
authors.lastname: Remppis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000502:physiology*; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D004789:Enzyme Activation; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D020935:MAP Kinase Signaling System; D008858:Microscopy, Phase-Contrast; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D009418:S100 Proteins; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014343:Trypan Blue / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D002135:Calcium-Binding Proteins; D002966:Clathrin; D009418:S100 Proteins; C110294:S100A1 protein; D013778:Tetrazolium Salts; D013844:Thiazoles; D003847:Deoxyglucose; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; C022616:thiazolyl blue; D014343:Trypan Blue; D002118:Calcium