High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Microbiome Research

Background:

• Trimethylamine N-oxide (TMAO), a metabolite from gut microbes, is linked to cardiovascular diseases (CVDs).
• The precise molecular mechanisms by which TMAO promotes atherosclerosis and CVD progression remain incompletely understood.
• High-mobility group box protein 1 (HMGB1), an inflammatory mediator, can disrupt endothelial cell-cell junctions, causing vascular hyperpermeability and endothelial dysfunction.

Purpose of the Study:

• To investigate whether TMAO-associated endothelial dysfunction is mediated by the activation of HMGB1.
• To elucidate the role of HMGB1 in the molecular pathways linking TMAO to endothelial dysfunction and vascular damage.

Main Methods:

• Endothelial cells were treated with TMAO, and HMGB1 expression was analyzed using biochemical assays and RT-PCR.
• The effect of glycyrrhizin, an HMGB1 inhibitor, on TMAO-induced changes was assessed.
• Expression of cell-cell junction proteins (ZO-2, Occludin, VE-cadherin) and toll-like receptor 4 (TLR4) was evaluated using Western blot and immunofluorescence.
• The impact of TLR4 inhibition via siRNA on TMAO-induced endothelial damage was examined.

Main Results:

• TMAO treatment dose-dependently increased HMGB1 expression in endothelial cells.
• Glycyrrhizin pretreatment abolished TMAO-induced HMGB1 production and attenuated the disruption of ZO-2, Occludin, and VE-cadherin.
• TMAO increased TLR4 expression, and TLR4 inhibition protected endothelial cells from TMAO-induced tight junction disruption via HMGB1.

Conclusions:

• High-mobility group box protein 1 (HMGB1) is identified as a critical mediator in TMAO-induced endothelial dysfunction.
• The pathway involves TMAO-induced HMGB1 activation, leading to the disruption of endothelial cell-cell junctions.
• Toll-like receptor 4 (TLR4) plays a role in mediating the effects of TMAO on endothelial cells through HMGB1.