Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases.
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 hypoxia-inducible factor (HIF)-regulating O2-dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel mechanism of action. Hydralazine induced rapid and transient expression of HIF-1alpha 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-1alpha, evidence for HIF stabilization specifically by inhibition of PHD enzyme activity. In vivo, hydralazine induced HIF-1alpha 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.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
Hydralazine Hydralazine hydralazine prolyl hydralazine VEGF HIF PHD HIF Collagen prolyl hydroxylase hydralazine hypoxia-inducible factor HIF prolyl hydroxylase domain PHD HIF-1alpha HIF endothelin-1 adrenomedullin haem oxygenase 1 vascular endothelial growth factor hydralazine VEGF PHD HIF-1alpha HIF PHD HIF-1alpha VEGF prolyl hydroxylases hypoxia-inducible factor-1alpha vascular endothelial growth factor hydralazine Ca2+ hydralazine prolyl hydralazine O2 prolyl