Advanced Glycation End Products Induce Atherosclerosis via RAGE/TLR4 Signaling Mediated-M1 Macrophage...

Area of Science:

• Cardiovascular Biology
• Immunology
• Metabolic Disease Research

Background:

• Advanced glycation end products (AGEs) are implicated in the pathogenesis of atherosclerosis (AS).
• The precise mechanisms by which AGEs exacerbate AS, particularly in the context of diabetes, remain incompletely understood.
• Understanding these pathways is crucial for developing targeted therapies for diabetic cardiovascular complications.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying AGE-exacerbated atherosclerosis.
• To investigate the role of Receptor for AGEs (RAGE) and Toll-like receptor 4 (TLR4) signaling in this process.
• To determine the contribution of macrophage polarization and vascular smooth muscle cell (VSMC) phenotype switching.

Main Methods:

• Administration of a TLR4 inhibitor to type 2 diabetes mellitus (T2DM) with AS rats.
• In vitro studies using AGE-exposed macrophages with RAGE and TLR4 knockdown via siRNA.
• Evaluation of macrophage and VSMC phenotypes, inflammatory cytokine secretion, and signaling pathway activation (RAGE/TLR4/FOXC2/Dll4/Notch) using molecular biology techniques.

Main Results:

• TLR4 inhibition reduced arterial stenosis, M1 macrophage infiltration, and VSMC phenotype conversion in diabetic AS rats.
• RAGE and TLR4 silencing inhibited AGE-induced M1 polarization, cytokine release, and RAGE/TLR4/FOXC2 signaling impacting Dll4 expression.
• AGE-induced VSMC phenotypic conversion was mediated by macrophages through direct cell-to-cell contact via the Dll4/Notch pathway.

Conclusions:

• AGEs activate RAGE/TLR4/FOXC2 signaling, leading to high Dll4 expression in M1-polarized macrophages.
• These activated macrophages promote VSMC contractile-to-synthetic phenotype conversion via the Dll4/Notch pathway.
• Direct cell-to-cell contact is essential for AGE-induced macrophage-mediated VSMC phenotypic modulation in atherosclerosis.