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Impaired cardiac contractility response to hemodynamic stress in S100A1-deficient mice
Xiao-Jun Du1, Timothy J Cole, Nora Tenis
1Baker Medical Research Institute, Melbourne, Victoria 8008, Australia.
Insights
Mice lacking the S100A1 gene show impaired cardiac function under stress. High S100A1 protein levels are crucial for maintaining heart function during hemodynamic challenges.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Calcium Signaling
Background:
- Calcium (Ca2+) signaling is vital for heart muscle contraction and adapting to stress.
- S100A1 is a major cardiac EF hand Ca2+-binding protein.
Purpose of the Study:
- To investigate the role of S100A1 in cardiac contractility and adaptation to hemodynamic stress.
- To determine the effects of S100A1 gene deletion on cardiac function in mice.
Main Methods:
- Generated S100A1 gene-deficient (S100A1-/-) mice.
- Assessed cardiac function under baseline, beta-adrenergic stimulation, and pressure overload conditions.
- Analyzed cardiac contractility, relaxation rates, and Ca2+ sensitivity.
Main Results:
- S100A1-/- mice exhibited reduced contraction and relaxation rates with impaired Ca2+ sensitivity during beta-adrenergic stimulation.
- Loss of S100A1 led to deteriorated cardiac contractility after pressure overload, despite normal hypertrophy.
- Heterozygous mice showed impaired acute response but maintained function with S100A1 upregulation during chronic stress.
Conclusions:
- S100A1 protein is essential for cardiac reserve and adaptation to acute and chronic hemodynamic stress.
- High S100A1 levels are critical for maintaining in vivo cardiac function under stress.
- Unlike other models, S100A1 deficiency did not cause cardiac hypertrophy or dilation in aged mice.
Abstract:
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.