Abstract 536: Human Antigen R (HuR) in the Myofibroblasts is a Critical Regulator of Pressure-Overload Induced Cardiac Remodeling

Abstract

Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) and is an important target because excess ECM leads to a stiffened myocardium and worsens the prognosis of heart failure. Human Antigen R (HuR) is an RNA binding protein known to stabilize mRNA through binding to AU rich regions in the 3’UTR, and we have previously shown HuR to play a central role in the development of cardiac hypertrophy. To interrogate the role of HuR in cardiac fibrosis, we used both a small molecule inhibitor of HuR as well as an inducible genetic deletion of HuR in the activated cardiac myofibroblasts (iMF-HuR -/- ). Results using an in vitro scratch assay showed that primary adult cardiac fibroblasts treated with a small molecule inhibitor of HuR display a delayed wound healing response concomitant with a reduced expression of ECM remodeling genes. In vivo , we used an 8-week TAC (transverse aortic constriction) model of pressure overload to induce pathological cardiac remodeling. We hypothesized that deleting HuR in the activated fibroblasts would dampen myofibroblast-mediated ECM remodeling leading to a less stiff myocardium with reduced fibrotic burden and improved cardiac function in iMF-HuR -/- mice following pressure overload (TAC). However, echocardiography results show that cardiac function declined more rapidly in iMF-HuR -/- following TAC. The iMF-HuR -/- mice also had significantly enlarged hearts compared to the controls indicated by the heart weight/tibia length ratio. This suggests a critical role for HuR and myofibroblast activity in the early response to pressure overload. Future studies will focus on determining how the fibroblasts and the ECM composition/stiffness affect myocyte function in the early cardiac remodeling phase post-TAC and how HuR is involved in this relationship.