What is the clinical evidence from this study?

Study design: Other. Population: Pulmonary arterial hypertension (n=8). Intervention: Tetrathiomolybdate (TTM) and dietary copper restriction vs. Vehicle or normal diet. Primary outcome: Reversal of pulmonary hypertension and inhibition of endothelial cell proliferation.

December 9, 2011Open Access

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

Key Result

Copper chelation with tetrathiomolybdate reversed severe experimental pulmonary arterial hypertension in rats and significantly inhibited the proliferation of human pulmonary microvascular endothelial cells.

Structured PICO

Does copper restriction or chelation with tetrathiomolybdate prevent or reverse angioproliferation in pulmonary arterial hypertension?

Population

Rats with experimental pulmonary arterial hypertension and human pulmonary microvascular endothelial cells isolated from explanted lungs of control subjects and patients with pulmonary arterial hypertension

Intervention

Copper-depleted diet and copper chelation with tetrathiomolybdate

Outcome

Development and reversal of severe experimental pulmonary arterial hypertension and proliferation of human pulmonary microvascular endothelial cellssurrogate

Copper chelation reverses experimental pulmonary arterial hypertension and inhibits endothelial cell proliferation, highlighting a potential novel antiangiogenic therapeutic strategy.

Limitations

The study did not address whether high rates of cell proliferation require the continued presence of apoptotic cells or if remodeling involves a permanent phenotypic switch.
Did not address the possibility of immune modulation by copper restriction and TTM.
Potential toxicity to the right ventricle must be rigorously tested before TTM can be proposed as a novel therapeutic agent in PAH.

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.

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