Document Detail


Copper dependence of angioproliferation in pulmonary arterial hypertension in rats and humans.
MedLine Citation:
PMID:  22162909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-12-28
Journal Detail:
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:
Created Date:  2012-05-02     Completed Date:  2012-06-25     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  582-91     Citation Subset:  IM    
Affiliation:
Department of Pulmonary Medicine, VU University Medical Center, Amsterdam, The Netherlands. hj.bogaard@vumc.nl
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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

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