Abstract 272: miRNA-7 Leads to Enhanced Fibrosis in the Heart

Abstract

MicroRNA-7 (miR-7) is known to target epidermal growth factor receptors (EGFRs) in oncogenic cells however, less is known about its role and function in the heart. Our studies have identified reciprocal expression pattern for ERBB2 (a member of EGFR family) in the context of miR-7 expression in human heart failure and in mice post-TAC (Transverse Aortic Constriction). To directly determine the role of miR-7 in the heart, we generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of miR-7 (miR-7 Tg). miR-7 Tg mice are characterized by marked loss in ERBB2 expression compared to their wildtype littermate controls. Also, miR-7 Tg mice have age-dependent deterioration in cardiac dysfunction and is associated with dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS and 12 months - 24%FS) and yet, they survive over 18 months as assessed by Kaplan-Meier curves. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miR-7 Tg mice were subjected to TAC for two weeks. In contrast to the wild type littermates that showed significant hypertrophic response, miR-7 Tg mice have accelerated cardiac dysfunction and dilation following two weeks of TAC. Histological analysis shows increased collagen deposition in miR-7 Tg mice which is further accelerated following after TAC compared to their sham controls. These observations suggest that ERBB2 expression in the cardiomyocytes may play a critical role in delaying the pro-fibrotic response post-TAC by supporting an adaptive hypertrophic response in response to stress. Our study will discuss the mechanisms of increased fibrosis observed in miR-7 Tg mice subjected to TAC.