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Molecular and Cellular Biology, April 2002, p. 2821-2829, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2821-2829.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice

Xiao-Jun Du,1 Timothy J. Cole,1 Nora Tenis,2 Xiao-Ming Gao,1 Frank Köntgen,3,{dagger} Bruce E. Kemp,2,4 and Jörg Heierhorst2,4*

Baker Medical Research Institute, Melbourne, Victoria 8008,1 The Walter-and-Eliza-Hall Institute, Parkville, Victoria 3050 ,3 St. Vincent's Institute of Medical Research,2 Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria 3065, Australia4

Received 24 October 2001/ Returned for modification 10 December 2001/ Accepted 22 January 2002

Ca2+ signaling plays a central role in cardiac contractility and adaptation to increased hemodynamic demand. We have generated mice with a targeted deletion of the S100A1 gene coding for the major cardiac isoform of the large multigenic S100 family of EF hand Ca2+-binding proteins. S100A1-/- mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to ß-adrenergic stimulation that are associated with a reduced Ca2+ sensitivity. In S100A1-/- mice, basal left-ventricular contractility deteriorated following 3-week pressure overload by thoracic aorta constriction despite a normal adaptive hypertrophy. Surprisingly, heterozygotes also had an impaired response to acute ß-adrenergic stimulation but maintained normal contractility in response to chronic pressure overload that coincided with S100A1 upregulation to wild-type levels. In contrast to other genetic models with impaired cardiac contractility, loss of S100A1 did not lead to cardiac hypertrophy or dilation in aged mice. The data demonstrate that high S100A1 protein levels are essential for the cardiac reserve and adaptation to acute and chronic hemodynamic stress in vivo.

* Corresponding author. Mailing address: St. Vincent's Institute of Medical Research, 9 Princes St., Fitzroy, Victoria 3065, Australia. Phone: 61-3-9288-2503/2515. Fax: 61-3-9416-2676. E-mail: heier{at}ariel.its.unimelb.edu.au.

{dagger} Present address: Ozgene Pty. Ltd., Nedlands 6909, Western Australia, Australia.

Molecular and Cellular Biology, April 2002, p. 2821-2829, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2821-2829.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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