Abstract 60: Cardiac-specific Deletion of HuR Reduces Pathological Hypertrophy and Ventricular Remodeling Following Transverse Aortic Constriction

Abstract

The RNA binding protein HuR (Human antigen R) interacts with specific AU-rich domains in target mRNAs and is highly expressed in many cell types, including cardiomyocytes. However, the role of HuR in cardiac physiology is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic mouse cardiac myocytes at 8 weeks post-transverse aortic constriction (TAC). To determine the role of HuR in the development of cardiac hypertrophy, we have created a novel mouse model of cardiac myocyte-specific deletion of HuR. While cardiac-specific HuR deletion mice do not show an overt basal phenotype, they have preserved ejection fraction and reduced ventricular remodeling (hypertrophy and chamber dilation) compared to wild-type littermates at 8 weeks following TAC. Furthermore, HuR activation in the hypertrophic heart is strongly co-localized with regions of fibrosis. To this end, we show that HuR knockdown reduced hypertrophy and pro-fibrotic TGF-β gene expression in a phenylephrine treated neonatal rat ventricular myocyte (NRVM) model of hypertrophy. Thus, our results suggest that HuR activation in cardiac myocytes promotes pathogical hypertrophy and initiation of cardiac fibrosis via myocyte expression of TGF-β. These findings are significant as we have identified HuR as a novel mediator of pathological hypertrophy and suggest a pro-fibrotic role as a potential mechanism for this effect.