Abstract 394: Medium Chain Acyl-Coenzyme a Dehydrogenase Gene Therapy Induces Physiological Cardiac Hypertrophy and Protects Against Pathological Remodeling

Abstract

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, P<0.05), thicker left ventricular walls (rAAV6:control 0.82±0.03mm vs. rAAV6:MCAD 1.00±0.05mm, n=3-4/group, P<0.05), preserved systolic function, and no evidence of cardiac fibrosis, lung congestion or re-expression of the fetal genes atrial- and B- type natriuretic peptides. In a setting of pressure overload, mice that received rAAV:MCAD had less left ventricular fibrosis (3.4-fold lower vs. control, n=6-10/group, P<0.05), higher levels of SERCA2a gene expression, and a more favorable metabolic gene expression profile (increased gene expression of Pgc1α , Cpt1b and Glut4 , n=6-10/group, P<0.05) than control mice at the end of the treatment period. 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.