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

Abstract

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 Ca 2؉ -binding proteins. S100A1 ؊/؊ mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to ␤-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 ␤-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.

Targeting S100A1 in heart failure

“…In addition, after 3 weeks of transaortic constriction, SKO À/À mice showed increased susceptibility towards HF as indicated by left-ventricular contractility (dP/dtmax) and relaxation (dP/dtmin) in comparison with control mice, which showed a normal adaptive hypertrophy. 62 Still, cardiac remodeling and expression of hypertrophic markers as assessed by ANF expression and left ventricular mass remained equal. Surprisingly, heterozygous SKO +/ À mice with only half of the S100A1 protein level than control mice (WT) showed a similar response to acute b-AR stimulation than SKO À/À mice but displayed a compensated hypertrophy after transaortic constriction as control animals.…”

“…Surprisingly, heterozygous SKO +/ À mice with only half of the S100A1 protein level than control mice (WT) showed a similar response to acute b-AR stimulation than SKO À/À mice but displayed a compensated hypertrophy after transaortic constriction as control animals. 62 Subsequent analysis revealed an upregulation of S100A1 protein levels to those levels of control mice. Thus, it is tempting to speculate that normal left ventricular S100A1 expression levels are necessary to maintain cardiac function and an increase in S100A1 protein levels might be able to restore cardiac function after chronic afterload elevation.…”

“…Interestingly, first studies from Du et al 62 in homozygous S100A1 knockout (SKO À/À ) mice demonstrated no abnormal cardiac performance under basal conditions, but displayed impaired contractility after acute b-AR stimulation. In addition, after 3 weeks of transaortic constriction, SKO À/À mice showed increased susceptibility towards HF as indicated by left-ventricular contractility (dP/dtmax) and relaxation (dP/dtmin) in comparison with control mice, which showed a normal adaptive hypertrophy.…”

Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: Two ways to promote multifunctionality

“…S100 proteins in the cytosol act as intracellular calcium sensors and͞or calcium buffers. S100A1 is expressed exclusively in cardiac cells, where it has been implicated in a number of cardiomyopathies (81). S100A2, S100A6, and S100B are all present in the nucleus, where they control gene expression and are implicated in various forms of cancer.…”

“…S100A1 controls cardiac contractility and is associated with a number of cardiomyopathies (81). S100A2 is localized to the nucleus where it regulates transcription of various genes and acts as a tumor suppressor in breast cancer cells (82).…”