Aims: Cardiac remodeling as response to physiological and pathological stress is mediated by cardiac signaling pathways. Responsible proteins inside these mostly intracellular pathways are therefore potential therapeutic targets to be explored in vivo in terms of feasibility and outcome. It has previously been demonstrated that the overexpression of the exercise-induced CITED4 (CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain-4) provides some protection against adverse remodeling after ischemia/reperfusion injury (IRI). The aim of this study was to investigate in a preclinical setting whether somatic gene transfer of CITED4 preceded by ischemia/reperfusion injury benefits the myocardial recovery and cardiac function.

Methods and Results: Gene delivery of cardiomyocyte-specific CITED4 via intravenous AAV9 injections resulted in a 4-fold increase of cardiac CITED4 expression. This led to physiological cardiac growth in the treated wild type mice (C57BL/6J), shown after four weeks through increased heart weights and cardiomyocyte hypertrophy. They developed increased left ventricular mass and wall thickness without impairment of systolic function evaluated by echocardiography and without induction of pathologic remodeling gene expression markers.

Ischemia/reperfusion injury followed by AAV9-mediated CITED4 gene transfer 20 minutes later promoted a roughly 6-fold increase of cardiac CITED4 one week after surgery. CITED4-treated mice developed less apoptosis, fibrosis and inflammation, resulting in a smaller scar size. Compared to control mice receiving AAV9-GFP, cardiac function was improved in the CITED4-treated mice eight weeks after surgery.

Conclusion: Somatic gene transfer of CITED4 in a clinically relevant setting promotes physiological hypertrophy in mice sufficiently to mitigate adverse ventricular remodeling after ischemic injury. This study provides evidence of the feasibility of CITED4 gene therapy administered systemically post-reperfusion in a mouse IRI model. It delivers ultimately proof-of-concept for future research into novel exercise-based therapeutic targets for myocardial recovery after acute myocardial infarction.