Idiopathic pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arterial remodeling, increased RVSP, chronic inflammation and vasoconstriction. The familial form of PAH is usually due to mutations in the type 2 receptor for Bone Morphogenic Protein, BMPR2. Examination of the consequences of BMPR2 mutation in transgenic mice and in cell culture, corroborated by human data from the literature, implicates several pathways that converge to promote PAH. Our preliminary data indicate that BMPR2 mutation causes dephosphorylation of cofilin, likely through direct regulation of LIMK. Dephosphorylation of cofilin drives the glucocorticoid receptor (GR) into the nucleus, where in the absence of ligand it causes both abnormal signaling and glucocorticoid insensitivity. This paradoxically causes some GR-dependent agonist effects, thus weight gain and high blood glucose in BMPR2 mutant humans and mice, but causes inability to signal through others, leaving BMPR2 mutation carriers susceptible to the chronic inflammation, which glucocorticoids are meant to suppress. Glucocorticoid activation and elevated blood glucose can lead to elevated reactive oxygen species (ROS) through mitochondrial ROS production. Our data indicate that BMPR2 mutant mice have a ~2x increase in lipid peroxidation in whole lung, increased pulmonary vascular peroxidized lipid staining, and increased expression of ROS-responsive genes. Also, all BMPR2 mutations tested in cultured smooth muscle cells lead to a ~2x increase in peroxide formation, and RNA expression changes suggestive of increased ROS and a shift to aerobic glycolysis and glutaminolysis. Aberrant glucocorticoid receptor signaling leads to increased vascular adhesion and permeability by monocytes, and this in combination with increased ROS may drive recruitment of monocytes and alternative (M2) macrophage activation, which can drive pathologic changes to the pulmonary vasculature in their microenvironment. To synthesize these data, we hypothesize that the important early etiologic changes caused by BMPR2 mutation are aberrant glucocorticoid receptor signaling and increased ROS, which drive increased recruitment of monocytes, alternative (M2) macrophage activation, and remodeling of the pulmonary vasculature. This chronic inflammatory state in precapillary pulmonary arteries leads to PAH through loss of normal vasoreactivity, increased formation of thrombi, and a predisposition to proliferation caused by microenvironmental changes brought about by interactive signaling between BMPR2 mutant vascular cells and macrophages. This study will clarify the early molecular etiology of BMPR2-induced PAH, as well as providing information about BMP regulation of inflammation with implications to a host of diseases.

Public Health Relevance

This project tests the hypothesis that BMPR2 mutation predisposes to pulmonary hypertension by directly causing glucocorticoid receptor dysfunction leading to increased reactive oxygen species and recruitment of circulating cells to the lungs. A combination of cell culture and transgenic mouse model experiments will be used to test this hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095797-03
Application #
8286974
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (03))
Program Officer
Moore, Timothy M
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$501,704
Indirect Cost
$180,099
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
Rathinasabapathy, Anandharajan; Bryant, Andrew J; Suzuki, Toshio et al. (2018) rhACE2 Therapy Modifies Bleomycin-Induced Pulmonary Hypertension via Rescue of Vascular Remodeling. Front Physiol 9:271
Suzuki, Toshio; Carrier, Erica J; Talati, Megha H et al. (2018) Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 314:L118-L126
Rathinasabapathy, Anandharajan; Horowitz, Alana; Horton, Kelsey et al. (2018) The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury. Front Physiol 9:180
Hemnes, Anna R; Rathinasabapathy, Anandharajan; Austin, Eric A et al. (2018) A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J 51:
Pickworth, Josephine; Rothman, Alexander; Iremonger, James et al. (2017) Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling. Pulm Circ 7:768-776
Chen, Xinping; Austin, Eric D; Talati, Megha et al. (2017) Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects. Eur Respir J 50:
Egnatchik, Robert A; Brittain, Evan L; Shah, Amy T et al. (2017) Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension. Pulm Circ 7:186-199
Sakurai-Iesato, Yoriko; Kawata, Naoko; Tada, Yuji et al. (2017) The Relationship of Bone Mineral Density in Men with Chronic Obstructive Pulmonary Disease Classified According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Combined Chronic Obstructive Pulmonary Disease (COPD) Assessment System. Intern Med 56:1781-1790
Copeland, Courtney A; Han, Bing; Tiwari, Ajit et al. (2017) A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal. Mol Biol Cell 28:3095-3111

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