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 (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years. OBJECTIVE: We identified miR-489 and lncRNAs (cardiac hypertrophy related factor, 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 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 on angiotensin 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. Furthermore, we explored the molecular mechanism by which miR-489 expression is regulated and found that an lncRNA that we named 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 regulate Myd88 expression and hypertrophy. CONCLUSIONS: Our present study reveals a novel cardiac hypertrophy regulating model that is composed of CHRF, miR-489, and Myd88. The modulation of their levels may provide a new approach for tackling cardiac hypertrophy.
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 (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years. OBJECTIVE: We identified miR-489 and lncRNAs (cardiac hypertrophy related factor, 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 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 on angiotensin 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. Furthermore, we explored the molecular mechanism by which miR-489 expression is regulated and found that an lncRNA that we named 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 regulate Myd88 expression and hypertrophy. CONCLUSIONS: Our present study reveals a novel cardiac hypertrophy regulating model that is composed of CHRF, miR-489, and Myd88. The modulation of their levels may provide a new approach for tackling cardiac hypertrophy.