on October 11, 2007
Published online before print October 11, 2007, doi: 10.1161/ATVBAHA.107.148551
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Submitted on May 24, 2007
Accepted on September 26, 2007
A Novel Class of Prolyl Hydroxylase Inhibitors Induces Angiogenesis and Exerts Organ Protection Against Ischemia
Masaomi Nangaku ;
From the Division of Nephrology and Endocrinology (M.N.), University of Tokyo School of Medicine, Japan; the Institute of Medical Sciences (Y.I., S.T., T.M.), Divisions of Nephrology, Hypertension, and Metabolism and of Neurology, Tokai University School of Medicine, Kanagawa, Japan; the Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences (T.Y., O.O.), University of Tsukuba, Japan; the Center for Tsukuba Advanced Research Alliance (Y.F.-K.), University of Tsukuba, Japan; the Center for Tsukuba Advanced Research Alliance and JST-ERATO Environmental Response Project (M.Y.), University of Tsukuba, and the Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; the Service de Nephrologie (C.v.Y.d.S.), Universite Catholique de Louvain, Brussels, Belgium; and the Basic Medical Science and Molecular Medicine (N.H.), Tokai University School of Medicine, Kanagawa, Japan.
* To whom correspondence should be addressed. E-mail: t-miyata{at}is.icc.u-tokai.ac.jp.
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.
Key words: hypoxia • hypoxia inducible factor • structure based drug design • stroke • ischemia
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