| 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: Publisher |
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 (PA) system. Remodeling of the 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 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 PDGF. Forced depletion of CREB with 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 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 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 PA wall was suppressed by the superoxide dismutase mimetic, Tempol, which also prevented 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 Eb Reusch; Chrystelle V Garat |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-10 |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: - ISSN: 1533-4023 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1Cardiovascular Pulmonary Research and Division of 2Pulmonary Science and Critical Care Medicine, 3Endocrinology, and 4Cardiology, University of Colorado Denver, Aurora, CO 80045. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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