| Reduction of reactive oxygen species prevents hypoxia-induced CREB depletion in pulmonary artery smooth muscle cells. | |
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MedLine Citation:
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PMID: 21562428 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia-induced pulmonary arterial hypertension (PAH) is a deadly disease characterized by progressive remodeling and persistent vasoconstriction of the pulmonary arterial system. Remodeling of the pulmonary artery (PA) involves smooth muscle cell (SMC) proliferation, hypertrophy, migration, and elevated extracellular matrix (ECM) production elicited by mitogens and oxidants produced in response to hypoxic insult. We previously reported that the transcription factor cAMP response element binding protein (CREB) is depleted in medial PA SMCs in remodeled, hypertensive vessels in rats or calves exposed to chronic hypoxia. In culture, CREB loss can be induced in PA SMCs by exogenous oxidants or platelet-derived growth factor. Forced depletion of CREB with small interfering RNA (siRNA) in PA SMCs is sufficient to induce their proliferation, hypertrophy, migration, dedifferentiation, and ECM production. This suggests that oxidant and/or mitogen-induced loss of CREB in medial SMCs is, in part, responsible for PA thickening. Here, we tested whether oxidant scavengers could prevent the loss of CREB in PA SMCs and inhibit SMC proliferation, migration, and ECM production using in vitro and in vivo models. Exposure of PA SMCs to hypoxia induced hydrogen peroxide (H2O2) production and loss of CREB. Treatment of SMCs with exogenous H2O2 or a second oxidant, Sin-1, elicited CREB depletion under normoxic conditions. Exogenous H2O2 also induced SMC proliferation, migration, and increased elastin levels as did forced depletion of CREB. In vivo, hypoxia-induced thickening of the PA wall was suppressed by the superoxide dismutase mimetic, Tempol, which also prevented the loss of CREB in medial SMCs. Tempol also reduced hypoxia-induced SMC proliferation and elastin deposition in the PA. The data indicate that CREB levels in the arterial wall are regulated in part by oxidants produced in response to hypoxia and that CREB plays a crucial role in regulating SMC phenotype and PA remodeling. |
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Authors:
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Dwight J Klemm; Susan M Majka; Joseph T Crossno; John C Psilas; Jane E B Reusch; Chrystelle V Garat |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 58 ISSN: 1533-4023 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-11 Completed Date: 2011-12-19 Revised Date: 2012-09-25 |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 181-91 Citation Subset: IM |
Affiliation:
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Cardiovascular Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia / complications, metabolism* Blotting, Western Cell Culture Techniques Cell Hypoxia / drug effects Cell Movement / drug effects Cell Proliferation / drug effects Cells, Cultured Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors*, biosynthesis Free Radical Scavengers / pharmacology Hydrogen Peroxide / metabolism* Hypertension, Pulmonary / etiology, metabolism Male Muscle, Smooth, Vascular / cytology, drug effects, metabolism* Myocytes, Smooth Muscle / cytology, drug effects, metabolism* Pulmonary Artery / cytology, drug effects, metabolism* RNA, Small Interfering / pharmacology Rats Rats, Inbred WKY |
| Grant Support | |
ID/Acronym/Agency:
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P01 HL014985-37/HL/NHLBI NIH HHS; P01-HL014985/HL/NHLBI NIH HHS; R01 HL091105/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cyclic AMP Response Element-Binding Protein; 0/Free Radical Scavengers; 0/RNA, Small Interfering; 7722-84-1/Hydrogen Peroxide |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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