Role of Novel Fibroblast Specific Protease in Heart Failure
Charlotte Hawkins, BS; John Gehris, BS; Lisa Freeburg, BA; Amber Moore, BS; Sydney Womack; Francis G. Spinale, MD PhD
The development and progression of heart failure (HF) is a leading cause of disability, death, and healthcare expenditure in the United States. Historically, HF was viewed as a single disease process, significantly limiting the development of effective treatment strategies and therapies to prevent the progression of HF. Recently, two predominant HF phenotypes have been identified, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Successful advancements have been made in cancer therapeutics through the identification and targeting of unique cell types that emerge in the tumor microenvironment, such as Cancer-Associated Fibroblasts (CAFs). CAFs promote tissue remodeling and enhance tumor growth, invasion, and survival. Cardiac Fibroblasts (CFs), a similar cell type to CAFs, have been identified in the extracellular matrix (ECM) of the myocardium and respond to injury in a similar capacity to CAFs. Both CAFs and CFs are positive for Fibroblast Activation Protein (FAP), a serine protease that degrades critical ECM proteins. In previous cancer studies, FAP inhibition reduced ECM proteolysis, increased tissue matrix stability, and therefore serves as a promising target for therapeutics. The purpose of this study was to localize FAP activity and determine a timeline of FAP expression in the myocardium post-myocardial infarction (MI) in the HFrEF phenotype. Using a porcine model, LV tissue samples from MI and remote regions were analyzed using FAP activity assays. LV tissue samples from 28 days post-MI were analyzed from the reperfusion model and no reperfusion model MIs. There was a statistically significant increase in FAP activity in the MI region and remote region 28 days post-MI in both MI models (Reperfusion and No Reperfusion) compared to referent control which is suggestive of CF activation and is consistent with the proteolytic state resulting in post-MI remodeling. Additionally, no reperfusion MI LV tissue samples 3, 7, 14, and 28 days post-MI were analyzed to determine a timeline of FAP expression. The initial decrease in FAP activity followed by an increase in FAP activity suggests an optimal window of intervention to target FAP is between 7 and 10 days post-MI. These results further support the role of cardiac fibroblasts and FAP in post-MI remodeling and indicate FAP as a relevant target in the progression of HFrEF with the potential to leverage small molecule chemotherapeutics.