FAM114A1 Influences Cardiac Fibrosis by Regulating Angiotensin II Signaling in Cardiac Fibroblasts

Abstract

Cardiac fibrosis, a primary contributor to heart failure (HF) and sudden death, is considered as an important target for HF therapy. However, the signaling pathways that govern cardiac fibroblast (CF) function during cardiac fibrosis have not been fully elucidated. Here, we found that a functionally unannotated human myocardial infarction (MI) associated gene, family with sequence similarity 114 member A1 (FAM114A1), is induced in failing human and mouse hearts compared to non-failing hearts. Homozygous knockout of Fam114a1 (Fam114a1-/-) in the mouse genome reduces cardiac hypertrophy and fibrosis while significantly restores cardiac function in angiotensin (Ang) II- and MI-induced HF mouse models. Fam114a1 deletion antagonizes Ang II induced inflammation and oxidative stress. Using isolated mouse primary CFs in wild type and Fam114a1-/- mice, we found that FAM114A1 is a critical autonomous factor for CF proliferation, activation, and migration. We discovered that FAM114A1 interacts with angiotensin receptor associated protein (AGTRAP) and regulates the expression of angiotensin type 1 receptor (AT1R) and downstream Ang II signaling transduction, and subsequently influences pro-fibrotic response. Using RNA-Seq in mouse primary CFs, we identified differentially expressed genes including extracellular matrix proteins such as Adamts15. RNAi-mediated inactivation of Adamts15 attenuates CF activation and collagen deposition. Our results indicate that FAM114A1 regulates Ang II signaling and downstream pro-fibrotic and pro-inflammatory gene expression, thereby activating cardiac fibroblasts and augmenting pathological cardiac remodeling. These findings provide novel insights into regulation of cardiac fibrosis and identify FAM114A1 as a new therapeutic target for treatment of cardiac disease. SignificanceCardiac fibrosis is a hallmark of heart failure and angiotensin II signaling promotes pro-fibrotic response in the heart. This study is a pioneering investigation of the role of a functionally unknown protein FAM114A1. We show that FAM114A1 expression is induced in human and mouse failing hearts. Genetic ablation of FAM114A1 can effectively reduce cardiac fibrosis and pathological remodeling. Isolated cardiac fibroblasts from Fam114a1 knockout mice show reduced response to Ang II stimulation and compromised myofibroblast activation. Mechanistically, FAM114A1 binds to AGTRAP and influences AT1R protein expression, thereby enhancing angiotensin II signaling and pro-fibrotic response. Thus, FAM114A1 is a novel factor that modulates cardiac fibrosis and pharmacological inhibition of FAM114A1 may be a therapeutic strategy for the treatment of heart disease.