Fatty acid-binding proteins sustain endothelial glycolysis and arterial programming in pulmonary arterial hypertension

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Principal Investigator: Zhiyu  Dai
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2024
Award: $100,223
Funding agency: National Heart Lung and Blood Institute

Project Summary
 Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary
vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy,
failure, and premature death. The underlying mechanisms of vascular remodeling and obliterative
vascular lesion formation remain unclear. Fatty acid metabolism dysfunction is linked to PAH. However,
the mechanistic role of fatty acid metabolism in regulating pulmonary vascular remodeling in the
pathogenesis of PAH has not been reported. We hypothesize that endothelial fatty acid-binding proteins
4 and 5 (FABP4-5) regulate endothelial glycolysis and arterial programming through HIF-2a/SOX17
signaling which contributes to severe vascular remodeling in the pathogenesis of PAH. We will 1) define
the novel role of endothelial FABP4-5 in the pathogenesis of PAH using multiple transgenic animal
models. 2) delineate the cellular and molecular mechanisms that FABP4-5 induces arterial programming
and pathogenesis of PAH. Completing our proposed study will provide a novel therapeutic strategy for
the effective treatment of PAH in patients.

Terms: <Active Oxygen><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><Assay><Attenuated><Bioassay><Biological Assay><Blood Plasma><Blood Vessels><Blood capillaries><Cell Communication and Signaling><Cell Signaling><Cessation of life><Clinical><Common Rat Strains><Data><Death><Disease><Disorder><Distal><Dysfunction><E-FABP><Endothelial Cells><Endothelium><Exhibits><FABP5><FABP5 gene><Failure><Fatty Acid Metabolism Pathway><Fatty Acids><Functional disorder><Generations><Genes><Genetic><Glycolysis><Glycolysis Induction><Goals><Heart Hypertrophy><Hexadecanoates><Hexadecanoic Acid><Human><Hypertension><Injury><Intermediary Metabolism><Intracellular Communication and Signaling><KFABP><Lesion><Link><Lung><Lung Respiratory System><Mediating><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Murine><Mus><Muscle><Muscle Tissue><Oxygen Radicals><PA-FABP><Palmitates><Palmitic Acids><Pathogenesis><Pathogenicity><Pathology><Patients><Phenotype><Physiopathology><Plasma><Plasma Serum><Play><Population><Pro-Oxidants><Programmed Cell Death><Progressive Disease><Proliferating><Pulmonary Hypertension><Pulmonary Vascular Resistance><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Role><SOX17><SOX17 gene><SRY-Related HMG-Box Gene 17><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Specific qualifier value><Specified><Systolic Pressure><Transgenic Animals><Up-Regulation><Upregulation><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular remodeling><Ventricular><attenuate><attenuates><biological signal transduction><blood vessel disorder><capillary><cardiac hypertrophy><effective therapy><effective treatment><endothelial dysfunction><extracellular><fatty acid metabolism><fatty acid oxidation><fatty acid-binding proteins><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><hypoxia-induced pulmonary hypertension><hypoxic pulmonary hypertension><idiopathic pulmonary arterial hypertension><idiopathic pulmonary hypertension><injuries><lung vascular remodeling><metabolism measurement><metabolomics><metabonomics><mitochondrial><model of animal><mortality><mouse model><murine model><muscular><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><overexpress><overexpression><pathophysiology><premature><prematurity><primary pulmonary hypertension><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><pulmonary vascular remodeling><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><therapeutically effective><treatment strategy><vascular><vascular dysfunction><vasculopathy>