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.

Advances in Gene-Based Therapy for Heart Failure

“…Indeed, in heart failure, reduction in the expression of S100A1 has been reported. In a rat model of cryo-induced myocardial injury, gene transfer of S100A1 resulted in an increase in SERCA2a and RyR activities with improvement in intracellular calcium handling and an overall enhancement of both systolic and diastolic ventricular functions [87].…”

Schlüsselrolle des Ca2+ in der Herzinsuffizienz und mögliche neue therapeutische Ansatzpunkte

“…Ein Protein, das physiologischerweise als Aktivator der SERCA2a fungiert, ist das bei Herzinsuffizienz vermindert exprimierte Ca 2+ -bindende Protein S100A1. Der Gentransfer des S100A1-Gens in Herzmuskelzellen der Ratte konnte eine bestehende kontraktile Dysfunktion attenuieren und die Ca 2+ -Transienten normalisieren [39]. Die Verwendung eines rekombinanten adenoassoziierten Virus (rAAV) stellte im Tiermodell eine langfristig stabile Expression des S100A1-Proteins sicher und führte zusätzlich zu einer Rückbildung des linksventrikulären Remodellings [40].…”

“…S100A1 werden hierbei zusätzlich positive Effekte auf die Na + -Homöosta-se, das im Sinne einer fetalen Genexpression alterierte Expressionsmuster sowie den Energiehaushalt der Zelle zugesprochen [39].…”

Parvalbumin Isoforms for Enhancing Cardiac Diastolic Function

“…Genetic regulation of Ca 2+ handling proteins, such as those increasing SERCA2a, sorcin, S100A1, or NCX expression and those removing the inhibition of PLN have been shown to mitigate diastolic and systolic dysfunction [36][37][38][39]. NCX has been shown to be elevated in HF and experimental NCX overexpression strategies have shown beneficial or deleterious effects in various HF models [40,41].…”