Abstract
ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl2, a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.
Highlights
ADAMTS1 was originally cloned from a murine colon carcinoma cell line [6]
We found that the exposure of endothelial cells to hypoxia up-regulated ADAMTS1 expression, and the transcriptional activation of ADAMTS1 was mediated by hypoxiainducible factor (HIF)-1, which binds to hypoxia response elements (HREs) in the promoter region of the ADAMTS1 gene
ADAMTS1 Expression Is Increased in Hypoxic Endothelial Cells—We first examined whether the expression of the ADAMTS1 gene is induced in hypoxic human umbilical vein endothelial cells (HUVEC)
Summary
ADAMTS1 was originally cloned from a murine colon carcinoma cell line [6]. Recently, it has been reported that a polymorphism of ADAMTS1 is closely associated with the occurrence of ischemic heart disease [7]. We have previously reported that ADAMTS1 was induced in the infarcted heart [10]; the regulatory mechanism of ADAMTS1 in ischemia is unknown. Low oxygen tension (hypoxia) affects endothelial cells in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins [11]. One mechanism of the regulation of gene expression in response to hypoxia is mediated by the transcriptional factor HIF-1 (hypoxia-inducible factor 1) [12]. Genes transactivated by HIF-1 include EPO (erythropoietin), glucose transporter 1, VEGF (vascular endothelial growth factor), and ET-1 (endothelin-1) [14, 15]. We found that the exposure of endothelial cells to hypoxia up-regulated ADAMTS1 expression, and the transcriptional activation of ADAMTS1 was mediated by HIF-1, which binds to HREs in the promoter region of the ADAMTS1 gene
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