title: Transgenic overexpression of the Ca2+-binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance.
abstract: S100A1, a Ca2+-sensing protein of the EF-hand family, is most highly expressed in myocardial tissue, and cardiac S100A1 overexpression in vitro has been shown to enhance myocyte contractile properties. To study the physiological consequences of S100A1 in vivo, transgenic mice were developed with cardiac-restricted overexpression of S100A1. Characterization of two independent transgenic mouse lines with approximately 4-fold overexpression of S100A1 in the myocardium revealed a marked augmentation of in vivo basal cardiac function that remained elevated after beta-adrenergic receptor stimulation. Contractile function and Ca2+ handling properties were increased in ventricular cardiomyocytes isolated from S100A1 transgenic mice. Enhanced cellular Ca2+ cycling by S100A1 was associated both with increased sarcoplasmic reticulum Ca2+ content and enhanced sarcoplasmic reticulum Ca2+-induced Ca2+ release, and S100A1 was shown to associate with the cardiac ryanodine receptor. No alterations in beta-adrenergic signal transduction or major cardiac Ca2+-cycling proteins occurred, and there were no signs of hypertrophy with chronic cardiac S100A1 overexpression. Our findings suggest that S100A1 plays an important in vivo role in the regulation of cardiac function perhaps through interacting with the ryanodine receptor. Because S100A1 protein expression is down-regulated in heart failure, increasing S100A1 expression in the heart may represent a novel means to augment contractility.
authors.affiliation: Medizinische Universitätsklinik und Poliklinik III, Universität zu Heidelberg, 69115 Heidelberg.
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Andrew
authors.initials: A
authors.lastname: Remppis
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Eva
authors.initials: E
authors.lastname: Löffler
authors.forename: Philipp
authors.initials: P
authors.lastname: Ehlermann
authors.forename: Juliane
authors.initials: J
authors.lastname: Bernotat
authors.forename: Christiane
authors.initials: C
authors.lastname: Kleuss
authors.forename: Jörg
authors.initials: J
authors.lastname: Heierhorst
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz
authors.forename: Henning
authors.initials: H
authors.lastname: Witt
authors.forename: Peter
authors.initials: P
authors.lastname: Karczewski
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Duncan
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004452:Echocardiography; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D009418:S100 Proteins; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; D007545:Isoproterenol; D002118:Calcium