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Principal Investigator: JAMES D WEST
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2022
Award: $662,881
Funding agency: National Heart Lung and Blood Institute
Project Summary:
ACE2 shows tremendous promise in the treatment of pulmonary arterial hypertension (PAH). It
corrects many of the molecular defects caused by the most common heritable cause of disease,
BMPR2 mutation. It has reversed disease in a variety of animal models of PAH, including heritable,
hypoxic, and inflammatory models. We have tested it acutely in human idiopathic PAH patients, and
shown a variety of hemodynamic and molecular improvements, including a 40% improvement in
cardiac output with associated reduction in pulmonary vascular resistance. Unfortunately, because of
difficulties with both synthesis and delivery, it will be difficult to translate to common use.
Understanding key mediators of its effect is thus the primary barrier to effective translation of this
extraordinarily promising intervention. The proposed studies will identify the key molecular
mechanisms of downstream effect of ACE2 in the context of PAH, in regulation of the cytoskeleton
(aim 1), metabolism (aim 2), and improvements in right ventricle function in the heart (aim 3). The
unifying hypothesis to these aims is that ACE2’s therapeutic effect is primarily through MAS1-
mediated correction of cytoskeletal defects caused by suppressed BMPR2. These defects include
cell-cell junctions, mitochondrial dynamics, and regulation of eNOS. The project makes use of genetic
mouse models, including a new far-red reporter mouse which allows non-invasive imaging of heart
stress, patient-derived endothelial precursor cells, our new artificial arteriole system which accurately
reproduces pulse pressure, stiffness, flow, and shear in a cell culture system, thus combining human,
mouse, and new cell culture systems to answer these questions.
Terms: <3-mononitrotyrosine><3-nitrotyrosine><ACE2><Actins><Acute><Address><Agonist><AngII><Angiotensin I><Angiotensin II><Angiotensin II Receptor><Animal Model><Animal Models and Related Studies><Animals><BMPR-II><BMPR2><BMPR2 gene><BRK-3 protein><Blood Vessels><Bone Morphogenetic Protein Receptor, Type II (Serine/Threonine Kinase) Gene><Calcium Ion Signaling><Calcium Signaling><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Output><Cardiocyte><Causality><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Culture System><Cell Interaction><Cell Junctions><Cell Signaling><Cell-Cell Adhesion><Cell-to-Cell Interaction><Cells><Cellular Matrix><Chronic><Clinic><Clinical Trials><Critical Paths><Critical Pathways><Cytoskeletal System><Cytoskeleton><Defect><Development><Disease><Disorder><Dose><Drugs><Elements><Endothelium><Enzyme Gene><Enzymes><Erythrocuprein><Etiology><Family suidae><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Heart><Heart Muscle Cells><Heart myocyte><Hemocuprein><Heritability><Hour><Human><Hypoxia><Hypoxic><IPO-B><IRB><IRBs><IV Infusion><Indophenol Oxidase B><Inflammatory><Institutional Review Boards><Intercellular Junctions><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravenous infusion procedures><Knowledge><Link><Lung><Lung Respiratory System><MNSOD><Mammalian Cell><Manganese Superoxide Dismutase><Measures><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Medication><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Mitochondrial Superoxide Dismutase><Mn Superoxide Dismutase><Mn-SOD><Modeling><Modern Man><Molecular><Murine><Mus><Muscle Cells><Mutation><Myocytes><Oral><Oxidative Stress><Oxygen Deficiency><Pathway interactions><Patients><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Pigs><Process><Progress Reports><Prostacyclins><Prostaglandins I><Pulmonary Vascular Resistance><Pulse Pressure><Receptor Protein><Regulation><Renin-Angiotensin System><Reporter><Right Ventricles><Right Ventricular Function><Right ventricular structure><Rights><Rodent><Rodentia><Rodents Mammals><SOD2><SOD2 gene><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Suidae><Superoxide Dismutase><Superoxide Dismutase 2><Swine><System><Testing><Therapeutic Effect><Time><Translating><Translations><Vascular remodeling><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><analog><angiotensin converting enzyme 2><angiotensin converting enzyme II><animal data><arteriole><base><biological signal transduction><bone morphogenetic protein receptor II><bone morphogenetic protein receptor type II><capillary bed><cardiac function><cardiac imaging><cardiac scanning><cardiomyocyte><causation><cost><cytocuprein><cytokine><design><designing><developmental><disease causation><drug/agent><early clinical trial><early phase clinical trial><experiment><experimental research><experimental study><function of the heart><genome mutation><heart function><heart imaging><heart output><heart scanning><hemodynamics><idiopathic pulmonary arterial hypertension><idiopathic pulmonary hypertension><improved><improved functioning><in vivo evaluation><in vivo testing><interventional strategy><intracellular skeleton><intravenous infusion><mitochondrial><mitochondrial dysfunction><model of animal><model organism><mouse model><murine model><mutant><nitrotyrosine><non-invasive imaging><noninvasive imaging><pathway><phase 2 trial><phase II trial><polymerization><porcine><precursor cell><prevent><preventing><primary pulmonary hypertension><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><receptor><small molecule><suid><trafficking><type II BMP receptor><vascular><vascular constriction><vasoconstriction>