Abstract 16454: Microrna-7- Erbb2 Axis: A Critical Regulator of Cardiac Remodeling
miRNAs are short, non-coding RNAs that negatively regulate gene expression. In heart, miRNAs play an important role in altering pathological signaling resulting in cardiac remodeling transitioning into dilated cardiomyopathy (DCM). Our previously published comprehensive miRNA-microarray in end stage human heart failure elucidated significant alterations in 8 miRNAs, out of which 2 miRNAs (-7 & -378) were shown for the first time to have a role in heart failure. Through a combination of bioinformatics and proteomics approach, we identified tyrosine kinase receptor ERBB2, a member of the epidermal growth factor receptor family as one of the major targets of mir-7 in the mir-7 overexpressing stable cells. We find a reciprocal relationship between mir-7 and ERBB2 in end stage human heart failure, mir-7 overexpressing cells and transverse aortic constriction (TAC) mice hearts. Furthermore, antagomir of mir-7 resulted in higher ERBB2 levels as opposed to mir-7 overexpression. In addition, we identified MAP kinase p-38 pathway to be a critical regulator of mir-7-ERBB2 signaling and cardiac remodeling. Since the role of miRNA-7 in cardiac context is uknown, we generated cardiac specific mir-7 overexpressing transgenic (Tg) mice. Analysis of mir-7 Tg mice shows severe cardiac dilation and wall thinning by 9 months (Figure). mir-7 Tg mice have lower ERBB2 levels as compared to their littermate controls. Previous studies have shown that conditional deletion of ERBB2 in heart leads to dilated cardiomyopathy similar to mir-7-Tg mice. In conclusion, regulation of ERBB2 signaling by miRNA-7 is a unique mechanism in cardiac remodeling and understanding this pathway may provide potential novel therapeutic target. .
- © 2012 by American Heart Association, Inc.