Abstract 12692: MicroRNA-Regulated p53 Expression in Cardiac Hypertrophy That Transits to Heart Failure
The molecular mechanisms triggering heart failure (HF), the major cause of mortality/morbidity worldwide, are not fully known. Small conserved noncoding RNAs of ∼22 nucleotides, called microRNAs (miRNAs), reportedly are involved in cardiac diseases. But what the altered miRNAs do as cardiac hypertrophy (CH) worsens to HF is unknown. We aim to identify and define the role of the altered miRNAs that participate during progression of CH to HF. We identified a unique miRNA involved in HF by various means: transgenic mice overexpressing cardiac myotrophin (myo-Tg mice, developed in our laboratory), which develop CH that progresses to HF, mimicking all symptoms of human HF; transverse aortic constriction (TAC) mice; and tissue samples from excised human hearts with end-stage HF. Using a array platform containing >13,000 probes, global miRNA expression profiling of failing hearts of myo-Tg mice revealed significant (p<0.01) alteration of 6 miRNAs (3 each up-/downregulated, log2 differences >2.0 vs. wild-type control). In TAC mice, of these 6 candidate miRNAs, quantitative real-time PCR analysis showed significant (p<0.001) downregulation (0.78±0.18) in one miRNA, designated as miR-D2, vs. sham control (7.14±1.25). Similarly significant (p<0.001) miR-D2 downregulation occurred in human end-stage HF (0.0074±0.0006) vs. nonfailing hearts (0.014±0.001). Importantly, in myo-Tg mice, downregulation of miR-D2 expression arose as early as at initiation of CH, continuing to HF. TargetScan analysis and functional network predicted by Ingenuity Pathway AnalysisTM revealed p53 as a nodal molecule regulated by miR-D2. RNA hybrid analysis showed potential target binding sites of miR-D2 at the 3' UTR of p53 mRNA. We reported that upregulation of p53 expression occurs only during transition of CH to HF. Electrophoretic mobility shift assay showed that activation of p53 is associated with elevated p53 expression in HF. We showed that a longstanding deficiency of miR-D2 expression at initiation of CH leads to transition to HF by increased p53 expression. Our data suggest that miR-D2-regulated p53 expression and its signaling cascade drive the progress of CH to HF. This finding is expected to help designing/developing therapeutics to prevent/treat CH/HF.
- © 2010 by American Heart Association, Inc.