Published online before print June 10, 2004, doi: 10.1161/01.RES.0000134924.89412.70
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Submitted on June 9, 2003
Revised on May 14, 2004
Accepted on May 27, 2004
Novel Mechanism of Action for Hydralazine: Induction of Hypoxia-Inducible Factor-1 alpha, Vascular Endothelial Growth Factor, and Angiogenesis by Inhibition of Prolyl Hydroxylases
Helen J. Knowles ;
From the Cancer Research UK Molecular Oncology Laboratory (H.J.K., A.L.H.), Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford; and the Henry Wellcome Building of Genomic Medicine (Y.-M.T., D.R.M.), University of Oxford, Roosevelt Drive, Oxford, UK.
* To whom correspondence should be addressed. E-mail: harrisa{at}cancer.org.uk.
The vasodilator hydralazine, used clinically in cardiovascular therapy, relaxes arterial smooth muscle by inhibiting accumulation of intracellular free Ca2+ via an unidentified primary target. Collagen prolyl hydroxylase is a known target of hydralazine. We therefore investigated whether inhibition of other members of this enzyme family, namely the HIF-regulating O2-dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel mechanism of action. Hydralazine induced rapid and transient expression of HIF-1
and downstream targets of HIF (endothelin-1, adrenomedullin, haem oxygenase 1, and vascular endothelial growth factor [VEGF]) in endothelial and smooth muscle cells and induced endothelial cell-specific proliferation. Hydralazine dose-dependently inhibited PHD activity and induced nonhydroxylated HIF-1, evidence for HIF stabilization specifically by inhibition of PHD enzyme activity. In vivo, hydralazine induced HIF-1 and VEGF protein in tissue extracts and elevated plasma VEGF levels. In sponge angiogenesis assays, hydralazine increased stromal cell infiltration and blood vessel density versus control animals. Thus, hydralazine activates the HIF pathway through inhibition of PHD activity and initiates a pro-angiogenic phenotype. This represents a novel mechanism of action for hydralazine and presents HIF as a potential target for treatment of ischemic disease.
Key words: cardiovascular disease • iron chelation • ischemia • endothelial cells
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