Abstract P192: MicroRNA-199b Targets the Nuclear Kinase Dyrk1a in an Auto-Amplification Loop Promoting Calcineurin/NFAT Signaling

MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of ∼22 nucleotides in length, and growing evidence indicates that miRs are implicated in myocardial disease processes. A key pathway involved in heart failure consists of the phosphatase calcineurin and its downstream transcription factor Nuclear Factor of Activated T-cells (NFAT). We performed microRNA profiling in hearts from calcineurin transgenic mice and demonstrated that microRNA-199b (miR-199b) is a direct calcineurin/NFAT target gene. MiR-199b increases in expression in mouse and human heart failure, and targets the nuclear NFAT kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (Dyrk1a), constituting a pathogenic feed forward mechanism with impact on calcineurin-responsive gene expression. Interestingly, cardiac miR-199b levels inversely correlated with cardiac Dyrk1a expression in biopsies of failing human hearts secondary to ischemic heart disease or non-ischemic dilated cardiomyopathy. Furthermore, mutant mice overexpressing miR-199b or haploinsufficient for Dyrk1a are sensitized to calcineurin/NFAT signaling or pressure overload and exhibit stress-induced cardiomegaly by reduced Dyrk1a expression. From a therapeutic point of view, in vivo inhibition of miR-199b by a specific antagomir normalized Dyrk1a expression, reduced nuclear NFAT activity, and caused marked inhibition and even reversal of pre-established hypertrophy and fibrosis in mouse models of heart failure. Our results reveal that microRNAs impact cardiac cellular signaling and gene expression, and implicate miR-199b as a therapeutic disease target in heart failure.