Abstract 16000: Erbb2: A Target of Microrna-7 Regulates Cardiac Remodeling
microRNAs (miRNAs) are tiny regulatory molecules implicated in diverse aspects of cardiac function including pathological signaling that results in deleterious cardiac remodeling transitioning to dilated cardiomyopathy (DCM). Our previous comprehensive genome-wide miRNA-microarray on end stage human DCM samples identified alterations in miRNA-7 in addition to the other well described miRNAs Through a combination of bioinformatics and proteomics approach, we identified tyrosine kinase receptor ERBB2, a member of the epidermal growth factor receptor (EGFR) family as one of the major targets of miRNA-7 which was validated by using different cell lines stably overexpressing miRNA-7. Since ERBB2 is thought to be critical in cardiac remodeling following stress, we hypothesized that downregulation of miRNA-7 would upregulate critical molecules including ERBB2 to overcome the increases in mechanical load with acute and chronic cardiac stress. Consistently, we find reciprocal relationship between miRNA-7 and ERBB2 expression in end stage human heart failure, miRNA-7 overexpressing cells or in mice subjected to transverse aortic constriction (TAC). Concordantly, downregulation of ERBB2 expression observed with miRNA-7 overexpression could be rescued with miRNA-7 antagomir. Given that ERBB2 is a constitutively active receptor and plays a critical role in cardiac hypertrophic response post TAC, we generated transgenic mice with myocyte specific expression of miRNA-7 to determine the role of miRNA-7-ERBB2 axis in cardiac remodeling. Echocardiography shows absence of age-dependent cardiac hypertrophic response in miRNA-7 transgenic mice which are instead characterized by dilation suggesting the involvement of ERBB2 signaling in age dependent physiological hypertrophic response. We further identify that miRNA-7 mediated ERBB2 regulation to be critically regulated by MAP kinase-p38 pathway which may contribute to the age dependent physiological hypertrophy. In conclusion, determining mechanisms of miRNA-7-ERBB2 axis will provide insights into less understood regulation of physiological hypertrophic response observed with increasing mechanical load with age.
- © 2013 by American Heart Association, Inc.