| Activity of the Estrogen Metabolising Enzyme Cytochrome P450 1B1 Influences the Development of Pulmonary Arterial Hypertension. | |
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MedLine Citation:
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PMID: 22859684 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND: Pulmonary arterial hypertension (PAH) is a hyperproliferative vascular disorder predominantly observed in women. Estrogen is a potent mitogen in human pulmonary artery smooth muscle cells (hPASMCs) and contributes to PAH in vivo, however the mechanisms attributed to this causation remain obscure. Curiously, heightened expression of the estrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) is reported in idiopathic PAH (IPAH) and murine models of PAH. METHODS AND RESULTS: Here, we investigated the putative pathogenic role of CYP1B1 in PAH. Quantitative RT-PCR, immunoblotting and in situ analysis revealed that pulmonary CYP1B1 is increased in hypoxic PAH, hypoxic + SU5416 PAH and human PAH and highly expressed within the pulmonary vascular wall. PAH was assessed in mice via measurement of right ventricular hypertrophy, pulmonary vascular remodelling and right ventricular systolic pressure. Hypoxic PAH was attenuated in CYP1B1-/- mice and the potent CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS; 3mg/kg/day i.p.) significantly attenuated hypoxic PAH and hypoxic + SU5416 PAH in vivo . TMS also abolished estrogen-induced proliferation in hPASMCs and PAH-PASMCs. The estrogen metabolite 16α-hydroxyestrone provoked hPASMC proliferation and this mitogenic effect was greatly pronounced in PAH-PASMCs. ELISA analysis revealed that 16α-hydroxyestrone concentration was elevated in PAH, consistent with CYP1B1 over-expression and activity. Finally, administration of the CYP1B1 metabolite 16α-hydroxyestrone (1.5mg/kg/day i.p.) caused the development of PAH in mice. CONCLUSIONS: Increased CYP1B1-mediated estrogen metabolism promotes the development of PAH, likely via the formation of mitogens including 16α-hydroxyestrone. Collectively, this study reveals a possible novel therapeutic target in clinical PAH. |
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Authors:
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Kevin White; Anne Katrine Johansen; Margaret Nilsen; Loredana Ciuclan; Emma Wallace; Leigh Paton; Annabel Campbell; Ian Morecroft; Lynn Loughlin; John D McClure; Matthew Thomas; Kirsty M Mair; Margaret R Maclean |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-8-2 |
Journal Detail:
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Title: Circulation Volume: - ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-8-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 University of Glasgow, Glasgow, United Kingdom; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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