ADAMTS1 is a unique hypoxic early response gene expressed by endothelial cells

Omer F. Hatipoglu, Satoshi Hirohata, M. Zeynel Cilkek, Hiroko Ogawa, Toru Miyoshi, Masanari Obika, Kadir Demircan, Ryoko Shihohata, Shozo Kusachi, Yoshifumi Ninomiya

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

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 ADAMTSI 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.

Original languageEnglish
Pages (from-to)16325-16333
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number24
DOIs
Publication statusPublished - Jun 12 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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