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Heme oxygenase‐1 serves as an important effector in the postischemic anti‐inflammatory phenotype induced by antecedent ethanol ingestion
Author(s) -
Yusof M,
Yamaguchi T,
Kamada K,
Gaskin F,
Durante W,
Korthuis R J
Publication year - 2006
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.20.4.a231-a
Subject(s) - chemistry , heme oxygenase , heme , pharmacology , downregulation and upregulation , enos , hemin , biochemistry , medicine , enzyme , nitric oxide synthase , gene
Since the catalytic products of heme oxygenase‐1 (HO‐1) activity exert powerful anti‐adhesive and anti‐oxidant properties, we postulated that ethanol (EtOH)‐induced HO‐1 expression serves as an effector of the postischemic anti‐inflammatory effects of this preconditioning stimulus. EtOH was administered to C57BL/6 mice by gavage at a dose that produced a peak plasma concentration of 45 mg/dl 30 min after ingestion. I/R was induced 24 hr later followed by assessment of leukocyte‐ and platelet‐endothelial interactions, HO‐1 activity (bilirubin assay), and HO‐1 expression (Western). I/R induced significant leukocyte and platelet adhesion, effects that were abolished by antecedent EtOH. Treatment with a HO‐1 inhibitor (SnPP‐IX) during I/R prevented the beneficial effects of EtOH‐PC. Alternatively, upregulation of HO‐1 with hemin mimicked the effects of antecedent EtOH. Although jejunal HO‐1 expression was not increased 24 hr after EtOH consumption, HO‐1 activity was increased during I/R. Pharmacologic inhibition studies indicated that EtOH‐induced increases in HO‐1 activity occur by an adenosine A 2 ‐receptor/eNOS‐dependent mechanism. The latter results are confirmed in WT mice and in eNOS‐/‐ mice. Taken together, our data indicate that HO‐1 functions as an effector of EtOH‐PC. Our work also suggests that a novel class of agents, HO‐1 inducers, may represent a new avenue for therapeutic intervention in I/R. Supported by DK 43785.