Fessel 2013 Pulm Circ
Fessel JP, Chen X, Frump A, Gladson S, Blackwell T, Kang C, Robinson L, Hemnes A, Austin E, West J (2013) Interaction between bone morphogenetic protein receptor type 2 (BMPR2) and estrogenic compounds in pulmonary arterial hypertension (PAH). Pulm Circ 3:564β77. |
Β» PMCID: PMC4070799 Open Access
Fessel JP, Chen X, Frump A, Gladson S, Blackwell T, Kang C, Robinson L, Hemnes A, Austin E, West J (2013) Pulm Circ
Abstract: The majority of heritable pulmonary arterial hypertension (HPAH) cases are associated with mutations in bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation carries about a 20% lifetime risk of PAH development, but penetrance is approximately three times higher in females. Previous studies have shown a correlation between estrogen metabolism and penetrance, with increased levels of the estrogen metabolite 16Ξ±-hydroxyestrone (16Ξ±OHE) and reduced levels of the metabolite 2-methoxyestrogen (2ME) associated with increased risk of disease. The goal of this study was to determine whether 16Ξ±OHE increased and 2ME decreased penetrance of disease in Bmpr2 mutant mice and, if so, by what mechanism. We found that 16Ξ±OHE[ratio]2ME ratio was high in male human HPAH patients. Bmpr2 mutant male mice receiving chronic 16Ξ±OHE had doubled disease penetrance, associated with reduced cardiac output. 2ME did not have a significant protective effect, either alone or in combination with 16Ξ±OHE. In control mice but not in Bmpr2 mutant mice, 16Ξ±OHE suppressed bone morphogenetic protein signaling, probably directly through suppression of Bmpr2 protein. Bmpr2 mutant pulmonary microvascular endothelial cells were insensitive to estrogen signaling through canonical pathways, associated with aberrant intracellular localization of estrogen receptor Ξ±. In both control and Bmpr2 mutant mice, 16Ξ±OHE was associated with suppression of cytokine expression but with increased alternate markers of injury, including alterations in genes related to thrombotic function, angiogenesis, planar polarity, and metabolism. These data support a causal relationship between increased 16Ξ±OHE and increased PAH penetrance, with the likely molecular mechanisms including suppression of BMPR2, alterations in estrogen receptor translocation, and induction of vascular injury and insulin resistanceβrelated pathways. β’ Keywords: Estrogen, Pulmonary hypertension, bmp, Metabolism, Insulin, wnt
β’ O2k-Network Lab: US TN Nashville Fessel JP
Labels: