Abstract 11297: Regulation of Myocardial Function by miR-1 Occurs Through Modulation of Sorcin and Ca2+ Signaling
Background: Dicer is markedly down-regulated in end-stage heart failure indicating that dysregulation of miRNA may play a significant role in the pathogenesis of myocardial dysfunction. The purpose of this study was to explore the role of miRNA in maintaining cardiac contractile function by using a tamoxifen-inducible, cardiac-specific Dicer knockout mouse and subsequently identify specific miRNAs and their relevant biological targets.
Methods and Results: Transgenic Myh6-Cre/Esr1 mice was successfully cross-bred to transgenic mice containing the Dicer flox/flox recombination. Induction of Dicer knockout by tamoxifen resulted in a dramatic and rapid decline in cardiac function assessed by echocardiography and invasive hemodynamic monitoring. This occured concurrent with reduction in levels of miR-1 by real-time PCR. The importance of miR-1 in maintaining normal cardiac function was established by in vivo injection of miR-1 antagomir into wild type mice, which replicated the cardiac-specific Dicer knockout phenotype. In both models depressed cardiac function was associated with up-regulation of Sorcin on Western blots. Sorcin is a ryanodine receptor 2 modulator and was subsequently identified as a miR-1 target in COS cells using luciferase construct containing UTR of Sorcin. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured HL-1 mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels. Rescue strategy was developed where in vivo delivery of siRNA directed against Sorcin prevented functional deterioration in both Dicer knockout mice and antagomir-1 injected wild type mice affirming Sorcin as the major mediator of the acute cardiomyopathy observed. Furthermore in vitro manipulation of miR-1 and Sorcin in HL-1 cells resulted in dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in human end-stage cardiomyopathy.
Conclusions: The findings demonstrate the importance of miR-1 in the maintenance of normal cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.
- © 2011 by American Heart Association, Inc.