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Prolyl Hydroxylase Inhibition Attenuates Hypoxia‐Induced Microvascular Inflammation Via iNOS Upregulation
Author(s) -
Parker Tuley R.,
Gonzalez Norberto C,
Holloway Naomi B,
Blanco V Gustavo,
Casillan Alfred J,
West Cameron E,
Michael Moncure,
Thomas James H,
Wood John G
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.731.2
Subject(s) - downregulation and upregulation , nitric oxide synthase , intravital microscopy , inflammation , hypoxia (environmental) , nitric oxide , chemistry , microcirculation , pharmacology , endocrinology , medicine , biochemistry , oxygen , organic chemistry , gene
Acute systemic hypoxia (Hx) promotes leukocyte adherence in post‐capillary venules of rats. When animals are chronically hypoxic, the initial microvascular inflammation resolves in part due to upregulation of inducible nitric oxide synthase (iNOS). Inhibition of prolyl hydroxylase (PHD) has been shown to increase hypoxia‐inducible factor‐1 (HIF‐1) levels, which can increase iNOS expression. Objective : This study evaluated whether inhibition of PHD attenuated Hx‐induced microvascular inflammation, and if upregulation of iNOS was involved. Methods : Intravital microscopy was used to measure leukocyte adherence in mesenteric venules of anesthetized rats. The PHD inhibitor EDHB was administered to rats 24 hrs prior to experiments. Results : Hx caused a rapid increase in leukocyte adherence in vehicle‐ but not in EDHB‐treated rats. Superfusion of the mesentery with the iNOS inhibitor L‐NIL caused a small but significant increase in adherent leukocytes during Hx in EDHB‐ but not vehicle‐treated rats. Conclusion : These results show that inhibition of PHD reduces Hx‐induced microvascular inflammation in part through iNOS upregulation, and are consistent with a HIF‐1‐dependent mechanism.