A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia

Masaomi Nangaku, Yuko Izuhara, Shunya Takizawa, Toshiharu Yamashita, Yoshiaki Fujii-Kuriyama, Osamu Ohneda, Masayuki Yamamoto, Charles Van Ypersele De Strihou, Noriaki Hirayama, Toshio Miyata

Research output: Contribution to journalArticlepeer-review

101 Citations (Scopus)

Abstract

OBJECTIVE - Hypoxia inducible factor (HIF) plays a pivotal role in the adaptation to ischemic conditions. Its activity is modulated by an oxygen-dependent hydroxylation of proline residues by prolyl hydroxylases (PHD). METHODS AND RESULTS - We discovered 2 unique compounds (TM6008 and TM6089), which inhibited PHD and stabilized HIF activity in vitro. Our docking simulation studies based on the 3-dimensional structure of human PHD2 disclosed that they preferentially bind to the active site of PHD. Whereas PHD inhibitors previously reported inhibit PHD activity via iron chelation, TM6089 does not share an iron chelating motif and is devoid of iron chelating activity. In vitro Matrigel assays and in vivo sponge assays demonstrated enhancement of angiogenesis by local administration of TM6008 and TM6089. Their oral administration stimulated HIF activity in various organs of transgenic rats expressing a hypoxia-responsive reporter vector. No acute toxicity was observed up to 2 weeks after a single oral dose of 2000 mg/kg for TM6008. Oral administration of TM6008 protected neurons in a model of cerebrovascular disease. The protection was associated with amelioration of apoptosis but independent of enhanced angiogenesis. CONCLUSIONS - The present study uncovered beneficial effects of novel PHD inhibitors preferentially binding to the active site of PHD.

Original languageEnglish
Pages (from-to)2548-2554
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume27
Issue number12
DOIs
Publication statusPublished - 2007 Dec

Keywords

  • Hypoxia
  • Hypoxia inducible factor
  • Ischemia
  • Stroke
  • Structure based drug design

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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