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Activation of Toll‐like Receptor 4 (TLR4) by High Mobility Group Box 1 (HMGB1) Leads to Oxidative Stress and Inflammation in Human Aortic Endothelial Cells
Author(s) -
Szasz Theodora,
Ogbi Safia,
Webb R. Clinton
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.1282.3
Subject(s) - hmgb1 , tlr4 , inflammation , nadph oxidase , endothelial dysfunction , oxidative stress , toll like receptor , biology , nox4 , superoxide dismutase , microbiology and biotechnology , downregulation and upregulation , innate immune system , chemistry , endocrinology , immunology , immune system , biochemistry , gene
Endothelial dysfunction is a central mechanism in the vascular pathology associated with hypertension, diabetes and atherosclerosis. Key mechanisms mediating endothelial dysfunction, such as reduced NO bioavailability and increased reactive oxygen species (ROS) production are intimately linked to vascular inflammation. Recent evidence supports activation of the innate immune system by endogenous damage‐associated molecular patterns (DAMPs) as a causative factor of the chronic low‐grade sterile inflammation associated with these conditions. High mobility group box 1 (HMGB1) is a chromatin protein and a DAMP which activates Toll‐like receptor 4 (TLR4), leading to increased NFκB signaling, ROS and cytokine production in immune cells. We hypothesized that TLR4 activation by HMGB1 in human aortic endothelial cells (HAEC) leads to activation of oxidative stress and inflammatory pathways and contributes to endothelial dysfunction. Recombinant human HMGB1, time and concentration‐dependently, induced activation of TLR4 in cultured HAEC as evidenced by expression of its downstream partner MyD88. HMGB1 increased ERK phosphorylation and nuclear translocation of NFκB, as well as increased expression of cyclooxygenase (COX‐1 and COX‐2). NO production was decreased in the presence of HMGB1, however no changes were observed in eNOS phosphorylation. HMGB1 also induced an increase in ROS production, increase in the expression of Nox4 subunit of NADPH oxidase and upregulation of the mitochondrial isoform of superoxide dismutase (MnSOD). These effects closely mimicked those induced by the TLR4 agonist lipopolysaccharide (LPS) and were inhibited or reversed by pretreatment of HAEC with the TLR4 antagonist CLI‐095. Our results suggest that HMGB1 may contribute to the endothelial dysfunction associated with diabetes and cardiovascular disease via activation of inflammatory and oxidative stress pathways. Support or Funding Information NIDDK