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.

Public Health Relevance

ACE2 shows tremendous promise in interventions against the molecular etiology of PAH, in cells, animals, and in our early human trials, but it will be difficult to bring to clinic because of difficulties in both synthesis and delivery. By the end of the proposed studies, we will understand the mechanisms by which ACE2 is improving both pulmonary vascular and right ventricular function, and we will have identified the molecular pathways by which these improvements are enacted. This will allow for the efficient design of small molecule interventions that target these critical pathways, and for better understanding of exactly which elements of PAH (vasoreactive, cytoskeletal, metabolic, oxidative stress, calcium signaling) are being corrected.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Xiao, Lei
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Vanderbilt University Medical Center
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West, James D; Carrier, Erica J (2018) Precision Modeling of Pulmonary Hypertension Pathology with Induced Pluripotent Stem Cell-derived Cells. Am J Respir Crit Care Med 198:154-155
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