ZFP36, an RNA Binding Protein that Regulates DNA Repair and Cell Proliferation in PAH

SUMMARY Pulmonary Arterial Hypertension (PAH) is a pulmonary vascular disease characterized by increased pulmonary arterial pressure. PAH patients are young, have poor life quality, and have a short life expectancy. This daunting fact underscores our need for innovative approaches in PAH. PAH arises from a pro-proliferative and anti-apoptotic phenotype of pulmonary arterial smooth muscle cells (PASMC), endothelial cells (PAEC), and fibroblast. Recent advances linked this phenotype to a genome-wide deregulation of gene expression. Therefore, it is imperative to decode the cause of this deregulation to find new therapies. Regulation of gene expression is governed, in large part, by one main class of protein: RNA-binding proteins (RBP). RBPs regulate the fate of hundreds of transcripts at once through the recognition of specific motifs that confer them a high therapeutic potential. However, limited data exist on their implication in PAH. Here, using large-scale transcriptomic data from PAH patients' lungs, and cultured PASMC and PAEC, we found ZFP36 an RBP increased in lungs and further enriched in PASMC but not in PAEC. We used computational biology to identify the targets of ZFP36 and characterize their functions in PAH-PASMC. Our data show that ZFP36 targets are lead actors in DNA repair and resistance to apoptosis (e.g. RFC3) and cell cycle (e.g. ANAPC4). In-vitro experiment on PAH-PASMC confirmed the up-regulation of ZFP36 targets and the role of ZFP36 in their up- regulation, as well as the role of ZFP36 in DNA repair and cell cycle. In addition, we found that inhibition of ZFP36 in Sugen/Hypoxia rats reduced PH severity.