Document Detail

Activity of the estrogen-metabolizing enzyme cytochrome P450 1B1 influences the development of pulmonary arterial hypertension.
MedLine Citation:
PMID:  22859684     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Pulmonary arterial hypertension (PAH) is a hyperproliferative vascular disorder observed predominantly in women. Estrogen is a potent mitogen in human pulmonary artery smooth muscle cells and contributes to PAH in vivo; however, the mechanisms attributed to this causation remain obscure. Curiously, heightened expression of the estrogen-metabolizing enzyme cytochrome P450 1B1 (CYP1B1) is reported in idiopathic PAH and murine models of PAH.
METHODS AND RESULTS: Here, we investigated the putative pathogenic role of CYP1B1 in PAH. Quantitative reverse transcription-polymerase chain reaction, immunoblotting, and in situ analysis revealed that pulmonary CYP1B1 is increased in hypoxic PAH, hypoxic+SU5416 PAH, and human PAH and is highly expressed within the pulmonary vascular wall. PAH was assessed in mice via measurement of right ventricular hypertrophy, pulmonary vascular remodeling, and right ventricular systolic pressure. Hypoxic PAH was attenuated in CYP1B1(-/-) mice, and the potent CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS; 3 mg · kg(-1) · d(-1) IP) significantly attenuated hypoxic PAH and hypoxic+SU5416 PAH in vivo. TMS also abolished estrogen-induced proliferation in human pulmonary artery smooth muscle cells and PAH-pulmonary artery smooth muscle cells. The estrogen metabolite 16α-hydroxyestrone provoked human pulmonary artery smooth muscle cell proliferation, and this mitogenic effect was greatly pronounced in PAH-pulmonary artery smooth muscle cells. ELISA analysis revealed that 16α-hydroxyestrone concentration was elevated in PAH, consistent with CYP1B1 overexpression and activity. Finally, administration of the CYP1B1 metabolite 16α-hydroxyestrone (1.5 mg · kg(-1) · d(-1) IP) 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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-02
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-28     Completed Date:  2012-11-13     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1087-98     Citation Subset:  AIM; IM    
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MeSH Terms
Anoxia / complications
Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors,  biosynthesis,  deficiency,  genetics,  physiology*
Cell Hypoxia
Cells, Cultured / drug effects,  metabolism
Chronic Disease
Enzyme Induction
Estradiol / pharmacology
Estrogens / metabolism*
Hydroxyestrones / metabolism,  pharmacology,  toxicity
Hypertension, Pulmonary / chemically induced,  enzymology*,  etiology,  pathology
Hypertrophy, Right Ventricular / enzymology
Lung / enzymology,  pathology
Mice, Knockout
Myocytes, Smooth Muscle / metabolism,  pathology
Pulmonary Artery / enzymology*,  pathology
Reverse Transcriptase Polymerase Chain Reaction
Stilbenes / pharmacology
Grant Support
FS/10/019/28205//British Heart Foundation; RG/11/7/28916//British Heart Foundation; //Biotechnology and Biological Sciences Research Council; //British Heart Foundation; //Medical Research Council
Reg. No./Substance:
0/2,4,3',5'-tetramethoxystilbene; 0/Estrogens; 0/Hydroxyestrones; 0/Stilbenes; 18186-49-7/16-hydroxyestrone; 4TI98Z838E/Estradiol; EC Hydrocarbon Hydroxylases; EC P-450 CYP1B1
Comment In:
Circulation. 2012 Aug 28;126(9):1016-9   [PMID:  22859685 ]

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