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Introduction: Gene-based therapies represent a realistic and feasible avenue for the treatment of cardiac disease. We previously demonstrated that activation of phosphoinositide 3-kinase [P13K(p110α)] was beneficial in heart failure mouse models and identified PI3K(p110α)-regulated mRNAs. We found that gene expression of medium chain acyl-coenzyme A dehydrogenase (MCAD) to be i) elevated in hearts with increased PI3K activity, ii) reduced in hearts with decreased PI3K activity, iii) reduced in settings of cardiac injury, and iv) positively correlated with cardiac function. Aim: The aim of this study was to determine whether gene delivery of MCAD could attenuate pressure overload-induced pathological remodeling. Methods: Recombinant adeno-associated viral vectors (rAAV) encoding MCAD or a control (2x10 11 vector genomes) were delivered to normal adult mice (n=9) and mice with pre-existing pathological hypertrophy and cardiac dysfunction due to pressure overload, induced by transverse aortic constriction (TAC, n=16). Cardiac function was assessed by echocardiography. Molecular/histological analyses were performed on heart tissue. Results: rAAV6:MCAD delivery promoted physiological growth of the heart in normal mice. Treated mice had larger hearts (Heart weight/tibia length [HW/TL] of rAAV6:control 8.3±0.5 mg/mm vs. HW/TL of rAAV6:MCAD 10.1±0.5 mg/mm, n=4-5/group, Pvs. rAAV6:MCAD 1.00±0.05mm, n=3-4/group, Pvs. control, n=6-10/group, PPgc1α , Cpt1b and Glut4 , n=6-10/group, P Conclusion: In summary, we show that MCAD can promote physiological cardiac hypertrophy in normal mice, and can attenuate fibrosis in a mouse model of cardiac injury.

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.