P487Cardiomyocyte-specific overexpression of microRNA-30c leads to severe atrial and ventricular dilation

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Abstract

MicroRNA-30c (miR-30c) is one of the most highly expressed miRNAs in the heart. Its function in cardiac (patho-)physiology is unknown, but it is found to be downregulated in several models of heart failure, including human aortic stenosis patients and mouse models with aortic constriction.

To investigate the function of miR-30c in the heart we generated a cardiac-specific miR-30c overexpression model in mice. Two independent founder lines A and B (6- and 10-fold overexpression, respectively) were phenotyped at 2 months of age but revealed no difference in heart weight, left ventricular internal diameter (LVID) in systole or diastole, and fractional shortening (FS), as measured by echocardiography. There were no differences observed in fibrosis, and neither did we observe any ECG abnormalities at this age.

However, at 3 months of age, miR-30c transgenic mice start dying, with 50% mortality after 5 and 8 months in line B and A respectively. The hearts show severely enlarged right atria and ventricular dilation, accompanied by arrhythmias that are probably secondary to the structural abnormalities. Echocardiography at 5 month old mice from line A (N=5) shows a 29% increase in systolic LVID, indicative of LV dilation. Fractional shortening in this group is decreased by 18%. Also, ANF expression is upregulated 2,4-fold, indicating the onset of cardiac hypertrophy which may eventually lead towards overt heart failure. Additionally, experiments in line B show a 30-fold upregulation of ANF expression at 3,5 months of age, clearly indicating a more severe phenotype in this line explaining the faster progression towards heart failure.

The mechanism by which miR-30c might lead to this dilated phenotype is complex and seems to revolve around several hypertrophic pathways converging on nuclear NFAT activation. Further experiments are needed to identify the direct targets of miR-30 and the effect of miR-30c overexpression on the activity of these pathways.

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