Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor

Abstract

Renal endothelin-converting enzyme (ECE)-1 is induced in experimental diabetes and following radiocontrast administration, conditions characterized by renal hypoxia, hypoxia-inducible factor (HIF) stabilization, and enhanced endothelin synthesis. Here we tested whether ECE-1 might be a HIF-target gene in vitro and in vivo. ECE-1 transcription and expression increased in cultured vascular endothelial and proximal tubular cell lines, subject to hypoxia, to mimosine or cobalt chloride. These interventions are known to stabilize HIF signaling by inhibition of HIF-prolyl hydroxylases. In rats, HIF-prolyl-hydroxylase inhibition by mimosine or FG-4497 increased HIF-1α immunostaining in renal tubules, principally in distal nephron segments. This was associated with markedly enhanced ECE-1 protein expression, predominantly in the renal medulla. A progressive and dramatic increase in ECE-1 immunostaining over time, in parallel with enhanced HIF expression, was also noted in conditional von Hippel-Lindau knockout mice. Since HIF and STAT3 are cross-stimulated, we triggered HIF expression by STAT3 activation in mice, transfected by or injected with a chimeric IL-6/IL-6-receptor protein, and found a similar pattern of enhanced ECE-1 expression. Chromatin immunoprecipitation sequence (ChIP-seq) and PCR analysis in hypoxic endothelial cells identified HIF binding at the ECE-1 promoter and intron regions. Thus, our findings suggest that ECE-1 may be a novel HIF-target gene.

Adaptive response to hypoxia and remote ischaemia pre‐conditioning: a new hypoxia‐inducible factors era in clinical medicine

“…, Khamaisi et al . ). The long list of acknowledged HIF‐target genes includes hexokinase, phosphofructokinase, aldolase, enolase, glucose transporters, adrenomedullin, erythropoietin (EPO), haeme‐oxygenase‐1 (HO‐1), carbonic anhydrase‐9 (CAIX), vascular endothelial growth factors (VEGF), transforming growth factor (TGF), insulin‐like growth factor (IGF) and its binding proteins, transferrin, transferrin receptor and ceruloplasmin, nitric oxide synthases, endothelin and endothelin converting enzyme‐1 (ECE‐1), adrenergic receptors, and many others (Schödel et al .…”

“…The HIFab heterodimers, either directly or through mediators such as miR-687, induce transient epigenetic changes in the DNA, with histone modification and chromosomal conformational changes, leading to transactivation of HIF-target genes . Over 2000 HREs were identified along the mouse genome and there are over 200 genes clearly controlled by HIF , Khamaisi et al 2015. The long list of acknowledged HIF-target genes includes hexokinase, phosphofructokinase, aldolase, enolase, glucose transporters, adrenomedullin, erythropoietin (EPO), haeme-oxygenase-1 (HO-1), carbonic anhydrase-9 (CAIX), vascular endothelial growth factors (VEGF), transforming growth factor (TGF), insulin-like growth factor (IGF) and its binding proteins, transferrin, transferrin receptor and ceruloplasmin, nitric oxide synthases, endothelin and endothelin converting enzyme-1 (ECE-1), adrenergic receptors, and many others , Khamaisi et al 2015.…”

Cyclosporine A induces endothelin‐converting enzyme‐1: Studies in vivo and in vitro

“…Recently, we found that hypoxia triggers the induction of ET‐converting enzyme (ECE)‐1, a key moderator in the generation of ET‐1, via the inhibition if HIF‐prolyl hydroxylases (PHD), with subsequent stabilization hypoxia‐inducible factors (HIF) . We further documented altered renal microcirculation, hypoxia and HIF upregulation following CsA administration .…”

Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo

“…COX-2 and PGIS are enzymes with opposing actions in inflammation (He et al, 2010;Camacho et al, 2011). Besides VEGF, iNOS, ECE-1 and COX-2 are other target genes of HIFs in hypoxia (Branco-Price et al, 2012;Khamaisi et al, 2015;Zhao et al, 2015). Whether activated macrophages affect these factors in hypoxia-stimulated HCMECs via peroxynitrite is unknown.…”

“…In contrast to COX-2, prostacyclin synthase (PGIS) antagonizes inflammation and has cytoprotective properties (He et al, 2010;Camacho et al, 2011). In addition to VEGF, HIFs also contribute to the trans-activation of iNOS, ECE-1 and COX-2, which leads to injury (Branco-Price et al, 2012;Khamaisi et al, 2015;Zhao et al, 2015).…”