Zinc deficiency up-regulates ET-1 mediated secretion and endothelial cell migration through nuclear HIF-1 translocation.

Abstract

BACKGROUND AND OBJECTIVE\nZinc is involved in the expression and function of various transcription factors including the hypoxia-inducible factor-1 (HIF-1). HIF-1 and its target gene endothelin-1 (ET-1) are activated by intermittent hypoxia (IH), one of the main consequences of obstructive sleep apnea (OSA), and both play a key role in the cardiovascular consequences of IH. Since OSA and IH are associated with zinc deficiency, we investigated the effect of zinc deficiency caused by chelation on the HIF‑1‑ET-1 pathway and its functional consequences in endothelial cells.\n\n\nMETHODS\nPrimary human microvascular endothelial cells (HMVEC) were incubated with sub-micromolar doses of a zinc-specific membrane-permeable chelator N,N,N ,N -tetrakis (2-pyridylmethyl) ethylene diamine (TPEN, 0.5 µM) or ET-1 (0.01 µM) with or without bosentan, an antagonist of ET-1 receptors. HIF-1α was silenced by transfection with specific siRNA. Nuclear HIF-1 content was assessed by immunofluorescence microscopy and Western blot. Migratory capacity of HMVEC was evaluated with a wound healing scratch assay.\n\n\nRESULTS\nZinc chelation by TPEN exposure induced the translocation of the cytosolic HIF-1α subunit of HIF-1 to the nucleus as well as an HIF-1-mediated ET-1 secretion by HMVEC. Incubation with either TPEN and ET-1 increased endothelial wound-healing capacity. Both HIF-1α silencing or bosentan abolished this effect.\n\n\nCONCLUSION\nAltogether, the results suggest that zinc deficiency up-regulates ET-1 signaling through HIF-1 activation and stimulates endothelial cell migration suggesting an important role of zinc in the vascular consequences of IH and OSA mediated by the HIF-1-ET- signaling.