Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

Abstract

Cardiac-restricted overexpression of the Ca 2+ -binding protein S100A1 has been shown to lead to increased myocardial contractile performance in vitro and in vivo. Since decreased cardiac expression of S100A1 is a characteristic of heart failure, we tested the hypothesis that S100A1 gene transfer could restore contractile function of failing myocardium. Adenoviral S100A1 gene delivery normalized S100A1 protein expression in a postinfarction rat heart failure model and reversed contractile dysfunction of failing myocardium in vivo and in vitro. S100A1 gene transfer to failing cardiomyocytes restored diminished intracellular Ca 2+ transients and sarcoplasmic reticulum (SR) Ca 2+ load mechanistically due to increased SR Ca 2+ uptake and reduced SR Ca 2+ leak. Moreover, S100A1 gene transfer decreased elevated intracellular Na + concentrations to levels detected in nonfailing cardiomyocytes, reversed reactivated fetal gene expression, and restored energy supply in failing cardiomyocytes. Intracoronary adenovirus-mediated S100A1 gene delivery in vivo to the postinfarcted failing rat heart normalized myocardial contractile function and Ca 2+ handling, which provided support in a physiological context for results found in myocytes. Thus, the present study demonstrates that restoration of S100A1 protein levels in failing myocardium by gene transfer may be a novel therapeutic strategy for the treatment of heart failure.

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

“…In this context, the overexpression of Myoscape resulted in enhanced global calcium transients with higher calcium amplitudes and LTCC currents. These results were additive to the effects of isoproterenol, implying that Myoscape acts independently of the adrenergic control of LTCC activity via PKA-dependent phosphorylation91326. Conversely, Myoscape ablation reduced LTCC currents irrespective of beta-adrenergic costimulation, which is associated with reduced global calcium transients and impaired contractile performance of cardiomyocytes.…”

Targeting S100A1 in heart failure

“…First indirect immunofluorescent confocal microscopy studies for S100A1 in isolated adult ventricular CM unveiled a characteristic striated pattern with peaks at the junctional and longitudinal sarcoplasmic reticulum (SR). 38 Further co-localization and co-immunoprecipitation analysis confirmed S100A1 interaction with both the sarcoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) and the ryanodine receptor 2 (RyR2), already foreshadowing its importance for SR Ca 2+ handling. [39][40][41][42] These descriptive studies were followed by a comprehensive series of functional analysis in isolated SR vesicles and in isolated CM.…”

“…S100A1 was shown to interact with the SERCA2a/PLB complex in a Ca 2+ -dependent manner, thereby increasing its activity and augmenting SR Ca 2+ uptake as well as SR Ca 2+ load. [38][39][40][41][42][43][44] The interaction of S100A1 with SERCA2a and the regulation of SR Ca 2+ sequestration appeared independent of PLB/SERCA2a interaction (PLB/SERCA2a ratio remained unchanged), nor interfered with PLB activation (unchanged phosphorylation at residue Serine 16 or Threonine 17) by protein kinase A (PKA) or Ca 2+ /calmodulin (CaM) -dependent protein kinase II. 44 Applying a synthetic peptide harboring the C-terminal amino-acid residues 75-94 (S100A1ct), similar results were obtained, corroborating insights into Ca 2+ -dependent conformational changes and the importance of the C-terminal extension for distinct S100A1 protein functions.…”

“…44 Applying a synthetic peptide harboring the C-terminal amino-acid residues 75-94 (S100A1ct), similar results were obtained, corroborating insights into Ca 2+ -dependent conformational changes and the importance of the C-terminal extension for distinct S100A1 protein functions. 38 On the other hand, S100A1 was found to directly regulate RyR2 function both under systolic and diastolic conditions. 38,40,45 In experiments utilizing isolated SR vesicles, S100A1 reduced 3H-ryanodine binding to the RyR2 at about 150 nM Ca 2+ , but increased 3H-ryanodine binding at Ca 2+ levels exceeding 300 nM, pointing towards a potential biphasic effect of S100A1 on RyR2 activity.…”

“…38 On the other hand, S100A1 was found to directly regulate RyR2 function both under systolic and diastolic conditions. 38,40,45 In experiments utilizing isolated SR vesicles, S100A1 reduced 3H-ryanodine binding to the RyR2 at about 150 nM Ca 2+ , but increased 3H-ryanodine binding at Ca 2+ levels exceeding 300 nM, pointing towards a potential biphasic effect of S100A1 on RyR2 activity. 38 Translating these findings into a functional consequence, Voelkers et al 45 demonstrated a decrease in frequency and amplitude of SR Ca 2+ sparks and waves in saponin-skinned as well as in intact quiescent normal CM employing recombinant human S100A1 protein and viral-based S100A1 overexpression, respectively.…”