Abstract 3571: Acute Myocardial Dysfunction Following Cardiac-Specific Dicer Knockout Mediated by Sorcin Dysregulation
miRNA serve as negative gene regulators and play a role in diverse regulatory pathways including cardiac organogenesis, hypertrophy and remodeling. Dicer, a type III ribonuclease essential in miRNA processing, is markedly down-regulated in myocardial tissues obtained from patients with end-stage heart failure suggesting that dysregulation of miRNA plays a role in the pathogenesis of myocardial dysfunction. The purpose of this study was to assess the overall relevance of miRNA in maintaining normal cardiac function using a model of tamoxifen (TMX) inducible cardiac-specific Dicer-knockout. Myh6-Cre/Esr1;Dicer flox/flox mice were generated and cardiac-specific cre-mediated deletion of the floxed Dicer gene was confirmed. Echocardiographic analysis of cardiac function in TMX induced Myh6-Cre/Esr1;Dicer flox/flox mice (n=12) demonstrated rapid (by 5th day) and sustained reduction in systolic function. Fractional shortening and ejection fraction were significantly decreased along with increased systolic dimension and systolic volumes. Diastolic dimension and volume, stroke volume, cardiac output and heart rate were not affected. Cardiac function of Myh6-cre/Esr;Dicer+/flox heterozygote mice (n=9), Myh6-cre/Esr1 mice (n=9) and Dicer flox/flox mice (n=9) were not affected following TMX treatment. There was significant and persistent down-regulation of Dicer by real-time PCR and Western blots in the Myh6-Cre/Esr1;Dicer flox/flox hearts following TMX treatment with no effect in control mice. TaqMan microRNA assays for specific miRNAs demonstrated significant reductions in miR-1 levels that temporally correlated with both reduction in Dicer levels and suppressed cardiac function. A potential miR-1 target, Sorcin, a ryanodyne receptor modulator, was also shown to be highly up-regulated by Western blot shortly after induction of Dicer knock-out. The temporal correlation of Dicer knockout, miR-1 attenuation, Sorcin up-regulation and cardiac dysfunction supports a functional relationship indicating that miR-1 regulates the contractile state of the myocardium by affecting calcium signaling.