A Long Noncoding RNA, CHRF Regulates Cardiac Hypertrophy by Targeting miR-489

RATIONALE: Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. microRNAs and Long non-coding RNAs (LncRNAs) have various biological functions, and have been extensively investigated throughout the past years. OBJECTIVE: We identified miR-489 and LncRNAs (CHRF) from hypertrophic cardiomyocytes. Here, we tested the hypothesis that miR-489 and CHRF can participate in the regulation of cardiac hypertrophy in vivo and in vitro. METHODS AND RESULTS: A microarray was performed to analyze miRNAs in response to angiotensin II (Ang-II) treatment, and we found miR-489 was substantially reduced. Enforced expression of miR-489 in cardiomyocytes and transgenic overexpression of miR-489 both exhibited reduced hypertrophic response upon Ang-II treatment. We identified myeloid differentiation primary response gene 88 (Myd88) as a miR-489 target to mediate the function of miR-489 in cardiac hypertrophy. Knockdown of Myd88 in cardiomyocytes and Myd88 knockout mice both showed attenuated hypertrophic responses. Further, we explored the molecular mechanism by which miR-489 expression is regulated, and found that a long non-coding RNA that we named cardiac hypertrophy related factor (CHRF) acts as an endogenous 'sponge' of miR-489, which downregulates miR-489 expression levels. CHRF is able to directly bind to miR-489, and regulates Myd88 expression and hypertrophy. CONCLUSIONS: Our present study reveals a novel cardiac hypertrophy regulating model which is composed of CHRF, miR-489 and Myd88. Modulation of their levels may provide a new approach for tackling cardiac hypertrophy.