Pulmonary arterial hypertension (PAH) is a progressively fatal disease with a female predominance. We previously showed that human PAH is strongly associated with reduced expression of the estrogen metabolism gene CYP1B1 and increase in the estrogen metabolite 16?OHE, which is highly estrogenic. Both females and males with BMPR2-associated PAH (BMPR2-PAH) and idiopathic PAH have elevated 16?OHE. While Bmpr2 mutant mice develop PAH with variable penetrance induced, addition of 16?OHE significantly amplifies penetrance and PAH severity. However, both pharmacologic blockade of estrogens and estrogen receptor (ESR) knock down approaches prevent PAH development. The data thus suggest that increased 16?OHE (and perhaps other estrogens), via ESR signaling, contribute to PAH pathogenesis. Concurrent with the exploration of estrogen metabolites in PAH, we and others are actively exploring the association of altered energy metabolism, including insulin resistance, with PAH. Insulin resistance and abnormal energy metabolism are features of BMPR2-PAH and idiopathic PAH subtypes, despite a lack of overt clinical co-morbid conditions. Intriguingly, while 16?OHE is vasodilatory and anti-inflammatory (features that should reduce PAH), it has also been associated with molecular insulin resistance and metabolic disturbances, including reductions in PPAR? and GLUT4 expression, and reduced mitochondrial oxygen consumption rates. In preliminary studies, we found that estrogen antagonism in mice prevents PAH and these molecular defects. Exploring the possibility that 16?OHE drives PAH, we found that increased lung expression of the miR29 family, known to regulate energy metabolism, associates with PAH penetrance and is amplified by 16?OHE. Further, disruption of miR29 activity by a miR29 antagonist prevented PAH and preserved metrics of normal energy metabolism (including rescue of PPAR? and GLUT4) in Bmpr2 mutant mice treated with 16?OHE. Thus, 16?OHE may amplify PAH via miR29-associated PPAR? suppression and altered metabolism. We hypothesize that that highly estrogenic compounds, including 16?OHE, contribute to PAH by dysregulating pulmonary vascular energy metabolism via suppression of PPAR?. We will explore this hypothesis with three aims: (1) To determine whether the estrogen 16?OHE associates with insulin resistance and elevated miR29 levels in humans with PAH; (2) To test the hypothesis that 16?OHE dysregulates energy metabolism primarily through suppression of PPAR?; (3) To determine the mechanisms by which 16?OHE suppresses PPAR?. This proposal will elucidate the mechanisms by which a highly estrogenic sex hormone profile (e.g., towards highly estrogenic compounds such as 16?OHE) results in PAH via the promotion of systemic and molecular features of insulin resistance and other derangements in energy metabolism. Given that estrogens may support heart function but promote PAH, ways to precisely target the correct person, or the correct pathway, with estrogen-modifying therapy may be an important foundation for novel clinical trial design.

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Pulmonary arterial hypertension (PAH) is a devastating disease which occurs more often in females and lacks curative therapies. We and others have shown that certain types of estrogens contribute PAH risk. This proposal aims to identify novel therapeutic approaches by testing the hypothesis that highly estrogenic compounds, including 16?OHE, contribute to PAH by dysregulating pulmonary vascular energy metabolism via suppression of PPAR?.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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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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Yan, Ling; Cogan, Joy D; Hedges, Lora K et al. (2018) The Y Chromosome Regulates BMPR2 Expression via SRY: A Possible Reason ""Why"" Fewer Males Develop Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 198:1581-1583
Brittain, Evan L; Thennapan, Thennapan; Maron, Bradley A et al. (2018) Update in Pulmonary Vascular Disease 2016 and 2017. Am J Respir Crit Care Med 198:13-23
Austin, Eric D; Hamid, Rizwan (2018) Y Not? Sex Chromosomes May Modify Sexual Dimorphism in Pulmonary Hypertension. Am J Respir Crit Care Med 197:858-859