ETS-Related Gene (ERG) and Friend leukemia integration – 1 (FLI-1) Transcription Factors in the Precision Treatment of Pulmonary Arterial Hypertension and Pulmonary Fibrosis

Abstract

Pulmonary arterial hypertension (PAH) is a chronic debilitating cardiopulmonary disease characterized by abnormal remodeling of peripheral lung vasculature resulting in progressive vasoconstriction. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible disease that is often associated with significant morbidity and poor quality of life. The prognosis of PAH and IPF is poor and currently available medications focus on relieving symptoms and slowing down progression. Hence, there is a clear necessity to develop new therapies. ETS-related genes and Friend leukemia integration-1 (FLI-1) are transcription factors involved in angiogenesis, cellular homeostasis, vascular remodeling, and the genetic regulation of inflammation, apoptosis, and fibrosis seen in PAH and IPF. Simultaneous small-interfering-RNA (siRNA) knockdown of ERG and FLI-1 in human pulmonary artery endothelial cells (HPAEC) and human pulmonary microvasculature endothelial cells (HPMEC) has been associated with up-regulation of pro-inflammatory genes and interferon (IFN) pathway-related genes. Notably, the endothelium in normal lungs has also been shown to have high levels of nuclear ERG and Fli-1 compared to significantly lower levels in diseased lungs. Recently, ERG upregulation was found to promote liver homoeostasis by regulating canonical TGFβ1-SMAD signaling and promoting the SMAD1 pathway while repressing SMAD3 activity. Improvement in pulmonary fibrosis through medications that suppress the TGF-β1/Smad3 pathway has also been a subject of study. In this review, we hypothesize that targeting the regulation of ERG, FLI-1 and ERG-mediation of TGF-β1/Smad3 signaling may be a promising therapeutic strategy in PAH and IPF.