Abstract 12025: Fatty Acid-Binding Proteins Promote Pulmonary Arterial Hypertension via Upregulation of Endothelial Glycolysis

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: We hypothesis that endothelial fatty acid metabolism is critical for obstructive vascular remodeling in the pathogenesis of PAH. Methods: A severe mouse model of PH Egln1 Tie2Cre mice were bred with Fabp45 -/- mice to generate Egln1 Tie2Cre / Fabp45 -/- mice. Single-cell RNA sequencing (scRNA-seq) analysis and metabolomic analysis were used to profile the pulmonary cells in Egln1 Tie2Cre mice and Egln1 Tie2Cre / Fabp45 -/- mice. Human hPAEC from idiopathic PAH patients and healthy donors, monocrotaline (MCT)-induced and Sugen5416/hypoxia (SuHx)-induced PH rats were used to measure fatty acid-binding protein 4 and 5 (FABP4 and FABP5) expression. siRNA mediated knockdown of FABP4 and FABP5 and lentivirus mediated FABP4 and 5 overexpression were performed to study cell proliferation, apoptosis, glycolysis, fatty acid oxidation. Echocardiography, hemodynamics, histological and immunostaining assay were performed to evaluate the PH phenotypes. Results: Both FABP4 and 5 were highly induced in the ECs of Egln1 Tie2Cre mice and PAECs from IPAH patients, as well as the whole lungs of MCT and SuHx-induced PH rats. Knockdown or overexpression of FABP4-5 reduced or enhanced EC proliferation, starvation-induced Caspase 3/7 activity, glycolysis and fatty acid oxidation. Genetic deletion of Fabp4 and 5 in Egln1 Tie2Cre mice exhibited a reduction of right ventricular systolic pressure (RVSP), RV hypertrophy, and attenuation of pulmonary vascular remodeling, prevention of right heart failure. Fabp4-5 deletion also normalized EC glycolysis gene programming, reduced HIF-2a expression and endothelial proliferation in Egln1 Tie2Cre mice. Conclusions: FABP4 and 5 control EC glycolysis and contribute to the development of severe PH.