Copper Dependence of Angioproliferation in Pulmonary Arterial Hypertension in Rats and Humans

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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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
Original languageEnglish
Pages (from-to)582-591
JournalAmerican journal of respiratory cell and molecular biology
Issue number5
Publication statusPublished - 2012

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