Abstract:
RATIONALE:17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling. OBJECTIVES:To determine the mechanism by which E2 exerts protective effects in HPH. METHODS:Male rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells. MEASUREMENTS AND MAIN RESULTS:E2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation. CONCLUSIONS:E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.
journal_name
Am J Respir Crit Care Medauthors
Lahm T,Albrecht M,Fisher AJ,Selej M,Patel NG,Brown JA,Justice MJ,Brown MB,Van Demark M,Trulock KM,Dieudonne D,Reddy JG,Presson RG,Petrache Idoi
10.1164/rccm.201107-1293OCsubject
Has Abstractpub_date
2012-05-01 00:00:00pages
965-80issue
9eissn
1073-449Xissn
1535-4970pii
rccm.201107-1293OCjournal_volume
185pub_type
杂志文章abstract::Although skeletal muscle abnormalities have been described in association with human immunodeficiency virus (HIV), the effects of HIV infection on respiratory muscle function have not been well characterized. We hypothesized that HIV+ individuals may develop respiratory muscle weakness and that respiratory muscle dysf...
journal_title:American journal of respiratory and critical care medicine
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doi:10.1164/ajrccm.155.3.9116990
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