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Principal Investigator: VINICIO A DE JESUS PEREZ
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $539,264
Funding agency: National Heart Lung and Blood Institute
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated
pulmonary pressures and right heart failure resulting in high morbidity and mortality. The pathologic hallmark of
PAH is progressive loss and obstructive remodeling of lung microvessels unresponsive to available therapies.
Studies by our group and others have shown that pulmonary microvascular endothelial cells (PMVECs) derived
from PAH patients are highly susceptible to apoptosis and have a lower capacity to form blood vessels (i.e.,
angiogenesis). Fatty acid oxidation (FAO) is an essential energy source for PMVECs that requires metabolic
coupling of mitochondria and endoplasmic reticulum (ER). Metabolic reprogramming characterized by high
glycolysis, reduced FAO, and mitochondrial/ER dysfunction is a key pathological feature of PAH PMVECs linked
to oxidative stress, endothelial dysfunction, and reduced angiogenesis. Our group has shown that reduced
activity of bone morphogenetic protein receptor 2 (BMPR2), the most common genetic cause of hereditary and
sporadic PAH, promotes metabolic reprogramming but, given the low penetrance of BMPR2 mutations,
alterations in other genes (i.e., “second hit”) are likely necessary for PAH development. In this proposal, we
will show that carboxylesterase 1 (CES1), a lipolytic enzyme responsible for releasing free fatty acids
from the ER to the mitochondria, is required for FAO and metabolic homeostasis in PMVECs. Our
preliminary studies show that CES1 knockdown in healthy PMVECs results in 1) high glycolysis, 2) reduced
FAO, 3) mitochondrial/ER dysfunction, and 4) oxidative stress. Furthermore, loss of CES1 exacerbates
metabolic reprogramming associated with BMPR2 insufficiency, and restoring CES1 expression improves PAH
PMVEC functional status. Based on our preliminary studies, we hypothesize that loss of CES1 in PAH
leads to endothelial dysfunction in PAH through metabolic reprogramming, lipotoxicity, and oxidative
stress. To test this, we propose the following aims: (1): Determine the mechanisms by which loss of CES1
results in metabolic reprogramming and lipotoxicity in PMVECs, (2) Determine whether loss of CES1 promotes
the development and severity of pulmonary hypertension and vasculopathy in mice, and (3) Determine the
contribution of BMPR2 insufficiency and epigenetic repression to reduced CES1 expression in PAH PMVECs.
Using the proposed approach, we will demonstrate that CES1 is essential for properly maintaining and repairing
the pulmonary endothelium and acts as a key modifier of BMPR2 signaling. Given the limited capacity of current
therapies to reverse endothelial dysfunction and prevent small vessel loss, therapeutic interventions that can
restore CES1 expression could serve as a novel treatment approach for PAH.
Terms: <Apoptosis><Apoptosis Pathway><Attenuated><Autoregulation><BMP receptor><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Sites><Blood Vessels><CES1><Carboxylesterase 1><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cellular Function><Cellular Physiology><Cellular Process><ChIP assay><Combining Site><Common Rat Strains><Coupling><DNA><Deoxyribonucleic Acid><Development><Disease><Disorder><Dysfunction><ER stress><Endoplasmic Reticulum><Endothelial Cells><Endothelium><Energy-Generating Resources><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Ergastoplasm><Fatty Acid Hydroperoxides><Fluorescent Probes><Free Fatty Acids><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genus Hippocampus><Glycolysis><Hereditary><Heterozygote><Histone Deacetylation><Homeostasis><Hypoxia><Hypoxic><Inherited><Intracellular Communication and Signaling><Intravenous><KO mice><Knock-out Mice><Knockout Mice><Life><Link><Lipid Hydroperoxide><Lipid Peroxides><Lipids><Lipoperoxides><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Measurement><Measures><Metabolic><Methylation><Mice><Mice Mammals><Mitochondria><Modeling><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><Nonesterified Fatty Acids><Null Mouse><Oxidative Stress><Oxygen Deficiency><Pathogenesis><Pathologic><Patients><Penetrance><Phenotype><Physiological Homeostasis><Physiopathology><Predisposition><Programmed Cell Death><Pulmonary Hypertension><Rat><Rats Mammals><Rattus><Reactive Site><Repression><Role><Seahorse><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Structure of parenchyma of lung><Subcellular Process><Susceptibility><Testing><Therapeutic Intervention><Time><Transcription Factor Proto-Oncogene><Transcription factor genes><Vascular remodeling><angiogenesis><attenuate><attenuates><biological signal transduction><bone loss><bone morphogenetic protein receptors><chromatin immunoprecipitation><developmental><endoplasmic reticulum stress><endothelial dysfunction><energy source><epigenetic regulation><epigenetically><fat metabolism><fatty acid oxidation><functional status><gene locus><genetic locus><genome mutation><genomic location><genomic locus><hemodynamics><heterozygosity><impaired pulmonary vascularization><improved><inhibitor><insight><intervention therapy><knock-down><knockdown><lipid metabolism><lipid peroxide><lipidomics><lung microvascular endothelial cells><lung pressure><lung repair><lung tissue repair><lung vascular disease><lung vascular endothelial cells><lung vascular remodeling><mitochondrial><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><prevent><preventing><promoter><promotor><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><pulmonary microvascular endothelial cells><pulmonary pressure><pulmonary repair><pulmonary vascular disease><pulmonary vascular disorder><pulmonary vascular dysfunction><pulmonary vascular endothelial cells><pulmonary vascular remodeling><pulmonary vasculopathy><pyrosequencing><response><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><social role><therapeutic agent development><therapeutic development><tool><transcription factor><vascular>