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Deficiency of Vascular TLR4 Protects Against Lipopolysaccharide‐Induced Endothelial Dysfunction and NADPH oxidase‐derived Superoxide
Author(s) -
Didion Sean
Publication year - 2016
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.30.1_supplement.1260.10
Subject(s) - superoxide , nadph oxidase , tlr4 , lipopolysaccharide , medicine , endocrinology , endothelium , endothelial dysfunction , chemistry , superoxide dismutase , nox4 , oxidase test , reactive oxygen species , pharmacology , receptor , biochemistry , oxidative stress , enzyme
The goal of this study was to test the hypothesis that homozygous toll‐like receptor 4 (TLR4) deficiency protects against lipopolysaccharide (LPS)‐induced endothelial dysfunction. Carotid arteries from wild‐type (TLR4+/+) and TLR4−/− mice were incubated in DMEM with either vehicle (saline) or LPS (0.05–0.50 μg/ml) for 22 hrs. LPS produced concentration‐dependent impairment (P<0.05) of endothelium‐dependent relaxation to acetylcholine in wild‐type mice. Both basal and NADPH‐stimulated superoxide levels were selectively increased in arteries from wild‐type mice treated with LPS. Tempol, a superoxide scavenger, improved endothelial responses and lowered superoxide levels in vessels from wild‐type mice treated with LPS. In contrast, LPS had no effect (P>0.05) on responses to acetylcholine or on basal or NADPH‐stimulated superoxide levels in TLR4−/− mice. The effects of LPS were selective for endothelium as responses to nitroprusside were unaltered (P>0.05) in either LPS‐treated wild‐type or TLR4−/− mice. Taken together, these genetic and pharmacological findings demonstrate that TLR4 expressed within the vascular wall contributes to LPS‐induced impairment of endothelial function, which is mediated in large part by increases in NADPH oxidase‐derived superoxide. Support or Funding Information Supported by NIH HL‐089884 and HL‐107632.