Impaired cardiac contractility response to hemodynamic stress in S100A1-deficient mice.
Ca(2+) 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 Ca(2+)-binding proteins. S100A1(-/-) mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to beta-adrenergic stimulation that are associated with a reduced Ca(2+) 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 beta-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.
Du
Xiao-Jun
XJ
Baker Medical Research Institute, Melbourne, Victoria 8008, Australia.
Cole
Timothy J
TJ
Tenis
Nora
N
Gao
Xiao-Ming
XM
Köntgen
Frank
F
Kemp
Bruce E
BE
Heierhorst
Jörg
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018390:Gene Targeting; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics; D006579:Heterozygote; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D009418:S100 Proteins; D013312:Stress, Physiological / Q000503:physiopathology; D016276:Ventricular Function
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D011943:Receptors, Adrenergic, beta; D009418:S100 Proteins; C110294:S100A1 protein; D007545:Isoproterenol