| Copper dependence of angioproliferation in pulmonary arterial hypertension in rats and humans. | |
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MedLine Citation:
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PMID: 22162909 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Obliteration of the vascular lumen by endothelial cell growth is a hallmark of many forms of severe pulmonary arterial hypertension. Copper plays a significant role in the control of endothelial cell proliferation in cancer and wound-healing. We sought to determine whether angioproliferation in rats with experimental pulmonary arterial hypertension and pulmonary microvascular endothelial cell proliferation in humans depend on the proangiogenic action of copper. A copper-depleted diet prevented, and copper chelation with tetrathiomolybdate reversed, the development of severe experimental pulmonary arterial hypertension. The copper chelation-induced reopening of obliterated vessels was caused by caspase-independent apoptosis, reduced vessel wall cell proliferation, and a normalization of vessel wall structure. No evidence was found for a role of super oxide-1 inhibition or lysyl-oxidase-1 inhibition in the reversal of angioproliferation. Tetrathiomolybdate inhibited the proliferation of human pulmonary microvascular endothelial cells, isolated from explanted lungs from control subjects and patients with pulmonary arterial hypertension. These data suggest that the inhibition of endothelial cell proliferation by a copper-restricting strategy could be explored as a new therapeutic approach in pulmonary arterial hypertension. It remains to be determined, however, whether potential toxicity to the right ventricle is offset by the beneficial pulmonary vascular effects of antiangiogenic treatment in patients with pulmonary arterial hypertension. |
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Authors:
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Harm J Bogaard; Shiro Mizuno; Christophe Guignabert; Aysar A Al Hussaini; Daniela Farkas; Gerrina Ruiter; Donatas Kraskauskas; Elie Fadel; Jeremy C Allegood; Marc Humbert; Anton Vonk Noordegraaf; Sarah Spiegel; Laszlo Farkas; Norbert F Voelkel |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-12-28 |
Journal Detail:
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Title: American journal of respiratory cell and molecular biology Volume: 46 ISSN: 1535-4989 ISO Abbreviation: Am. J. Respir. Cell Mol. Biol. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-02 Completed Date: 2012-06-25 Revised Date: 2013-05-22 |
Medline Journal Info:
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Nlm Unique ID: 8917225 Medline TA: Am J Respir Cell Mol Biol Country: United States |
Other Details:
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Languages: eng Pagination: 582-91 Citation Subset: IM |
Affiliation:
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Department of Pulmonary Medicine, VU University Medical Center, Amsterdam, The Netherlands. hj.bogaard@vumc.nl |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia / complications Caspases / metabolism Cell Division Cells, Cultured Chelating Agents / chemistry, therapeutic use Copper / administration & dosage, physiology* Diet Endothelium, Vascular / pathology* Enzyme Activation Humans Hypertension, Pulmonary / drug therapy, etiology, pathology* Immunohistochemistry Indoles / pharmacology Male Microvessels / pathology* Molybdenum / chemistry, therapeutic use Neovascularization, Pathologic / metabolism, pathology* Pyrroles / pharmacology Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI050094-09/AI/NIAID NIH HHS; R01 AI050094-10/AI/NIAID NIH HHS; T32 HL094290-03/HL/NHLBI NIH HHS; U19 AI077435-04/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chelating Agents; 0/Indoles; 0/Pyrroles; 71IA9S35AJ/Semaxinib; 7439-98-7/Molybdenum; 7440-50-8/Copper; 91U3TGV99T/tetrathiomolybdate; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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