title: Copper dependence of angioproliferation in pulmonary arterial hypertension in rats and humans.
abstract: 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.affiliation: Department of Pulmonary Medicine, VU University Medical Center, Amsterdam, The Netherlands. hj.bogaard@vumc.nl
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Bogaard
authors.forename: Shiro
authors.initials: S
authors.lastname: Mizuno
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.forename: Aysar A
authors.initials: AA
authors.lastname: Al Hussaini
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.forename: Gerrina
authors.initials: G
authors.lastname: Ruiter
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk Noordegraaf
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use; D003300:Copper / Q000008:administration & dosage / Q000502:physiology*; D004032:Diet; D004730:Endothelium, Vascular / Q000473:pathology*; D004789:Enzyme Activation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D000860:Hypoxia / Q000150:complications; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008982:Molybdenum / Q000737:chemistry / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002614:Chelating Agents; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D020169:Caspases