Abstract 20916: Therapeutic Cardiac-Targeted Delivery of Mir-1 Reverses Hypertrophy and Preserves Cardiac Function in a Pressure Overload Animal Model.
MicroRNAs have been shown to play an important role in modulating signaling pathways important in the pathogenesis of cardiac hypertrophy and heart failure. MiR-1 was found to be a key regulator of hypertrophy and its expression is inversely correlated to cardiac hypertrophy in murine models as well as in human disease states associated with myocardial hypertrophy. In this study we used a well-characterized pressure overload hypertrophy (POH) rat animal model to address a clinically relevant question of whether restoration of miR-1 in vivo by gene transfer could reverse hypertrophy in hearts with established pathology. Animals were subjected to ascending aortic banding (AAB) and two weeks later, when hypertrophy was evident, the animals were randomly chosen to receive either adeno-associated vector type 9 carrying miR-1 (AAV9.miR-1) (n=8) or control vector, AAV9.GFP (n=5) at 5 × 1011 vg (viral genomes) per animal. Seven weeks post gene transfer, echocardiographic analyses showed a regression of pathological LV hypertrophy with reduced incidents of heart failure in the AAV9.miR1 compared to AAV9.GFP infected animals. We observe a marked decrease in LV wall thickness in the AAV9.miR-1 group (2.27+0.055 vs 2.70+0.24 mm, p=0.02) and preservation of ventricular function as measured by fractional shortening (55.91±5.65% vs 36.42±5.66%, p=0.01). In addition, the reversal of LV remodeling was accompanied by normalization of the phenotype of the hypertrophic cardiomyocytes at the molecular level. We observed a significant decrease in the expression of fetal genes, such as ANF and β-MHC, as well as an increase in SERCA2a protein levels in the AAV9.miR-1 group in comparison to the control group. Functional studies performed on cardiomyocytes in vitro showed that overexpression of miR-1 negatively affected protein synthesis and the expression of fetal genes (ANF, βMHC), whilst SERCA2a expression was increased. In conclusion, AAV-mediated cardiac delivery of miR-1 before the onset of heart failure induced the regression of the pathological LV hypertrophy and preserved cardiac function that was mediated through the modulation of the fetal gene program and intracellular Ca2+ homeostasis. Targeting miR-1 may be an important strategy in reversing heart failure.
- © 2010 by American Heart Association, Inc.