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: Patrick Most, Andrew Remppis, Sven T Pleger, Eva Löffler, Philipp Ehlermann, Juliane Bernotat, Christiane Kleuss, Jörg Heierhorst, Patricia Ruiz, Henning Witt, Peter Karczewski, Lan Mao, Howard A Rockman, Sandra J Duncan, Hugo A Katus, Walter J Koch
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 36 Pg. 33809-17 (Sep 05 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12777394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Agonists
• Calcium-Binding Proteins
• Receptors, Adrenergic, beta
• Ryanodine Receptor Calcium Release Channel
• S100 Proteins
• S100A1 protein
• Isoproterenol
• Calcium

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Blotting, Northern
• Blotting, Western
• Calcium (metabolism)
• Calcium-Binding Proteins (genetics, physiology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Down-Regulation
• Echocardiography
• Isoproterenol (pharmacology)
• Kinetics
• Mice
• Mice, Transgenic
• Myocardial Contraction
• Myocardium (metabolism)
• Precipitin Tests
• Protein Binding
• Receptors, Adrenergic, beta (metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• S100 Proteins
• Sarcoplasmic Reticulum (metabolism)
• Signal Transduction
• Time Factors