Presenter: Dallen Calder
Authors: Dallen Calder, Thirupura Shankar, Stavros Drakos
Faculty Advisor: Stavros Drakos
Institution: University of Utah
Fibrosis is a major hallmark of heart failure (HF) progression and is characterized by fibroblast activation and excess extracellular matrix production. Left Ventricular Assist Devices (LVAD) are used as bridge-to-transplant therapy in HF patients and a small subset of these patients show both structural and functional improvement (referred to as responders). Some responders who originally displayed high cardiac fibrosis showed a significant reversal of fibrosis (n=6, p=0.0228) upon LVAD unloading. Using myocardial tissue acquired from these patients, RNA sequencing results identified a significant upregulation of Adipocyte enhancer binding protein (Aebp1). AEBP1 is a secreted protein that acts as a fibroblast activator upstream of ⍺SMA and has been repeatedly identified in lung and liver fibrosis studies as a potential therapeutic target.[1] [https://app.oxfordabstracts.com/stages/3110/submissions/new?behalf=false&fromDashboard=false&preview=false#_ftn1],[2] [https://app.oxfordabstracts.com/stages/3110/submissions/new?behalf=false&fromDashboard=false&preview=false#_ftn2],[3] [https://app.oxfordabstracts.com/stages/3110/submissions/new?behalf=false&fromDashboard=false&preview=false#_ftn3]However, the role of AEBP1 in cardiac fibrosis has not been well investigated. Using human cardiac fibroblasts (HCF), we showed that TGFβ stimulation causes fibroblast activation evident from increased expression of myofibroblast markers such as SM22, ⍺SMA and phosphorylated SMAD. In addition, we observed a significant increase in AEBP1 upon stimulation, suggesting that AEBP1 plausibly plays a role in fibroblast activation. To determine the role of AEBP1 in fibrosis progression we used in-vitrooverexpression and knock-down models. Overexpression experiments showed an upregulation of ⍺SMA in the unstimulated HCF population suggesting AEBP1 can independently trigger fibroblast activation. Similarly, AEBP1 knock-down experiments showed decreases in SM22 upon stimulation suggesting AEBP1 is essential to the process of fibroblast activation. Additionally, an AEBP1 knockdown mouse model will be used to elucidate the role of AEBP1 in the progression of fibrosis and the process of cardiac remodeling. While additional in-vivo experiments are necessary, our results suggest that AEBP1 is an essential component in the molecular processes that underlie fibrosis formation in the heart and is a potential therapeutic target for reverse remodeling.