A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia.
Arterioscler Thromb Vasc Biol
; 27(12): 2548-54, 2007 Dec.
Article
em En
| MEDLINE
| ID: mdl-17932321
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 ANDRESULTS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Isquemia Encefálica
/
Pró-Colágeno-Prolina Dioxigenase
/
Fármacos Neuroprotetores
/
Neovascularização Fisiológica
/
Indutores da Angiogênese
/
Inibidores Enzimáticos
/
Subunidade alfa do Fator 1 Induzível por Hipóxia
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Japão