Macrophage-AGE-RAGE Axis, A Promising Therapeutic Target in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy marked by sustained pulmonary vascular resistance, right ventricular (RV) pressure overload, and eventual RV failure and death.1,2 While current therapies improve vasodilation and short-term hemodynamics, they seldom address the underlying mechanisms of disease, especially inflammation-driven vascular remodeling.3,4 The study by Son et al. 5 proposes a novel therapeutic strategy targeting the macrophage-advanced glycation end products (AGE)receptor for advanced glycation end products (RAGE) axis with pyridoxamine (PM), an antiglycation agent and vitamin B6 analog.The authors show that activated macrophages are central to PAH progression by producing AGEs under hypoxic and inflammatory conditions.These AGEs increase RAGE expression and ligand production, including high mobility group box 1 (HMGB1) and S100 calciumbinding protein B (S100β), in both macrophages and pulmonary artery smooth muscle cells (PASMCs).This process promotes the release of inflammatory cytokines, PASMC proliferation, perivascular fibrosis, and vascular wall thickening, creating a feedforward loop that accelerates pulmonary vascular remodeling and RV overload.In monocrotaline and Sugen/hypoxia PAH animal models, PM reduced macrophage infiltration, decreased M1 (CD80) and M2 (CD206) macrophage activation, and lowered key inflammatory cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor-α).PM also downregulated RAGE and its ligands (AGEs, HMGB1, S100β) in lung tissue, indicating broad suppression of RAGE signaling.Structurally, PM reduced PASMC proliferation, medial wall thickness, and perivascular fibrosis.Functionally, PM decreased tricuspid regurgitation max pressure gradient, prolonged pulmonary valve acceleration time, and partially restored RV fractional area change and tricuspid annular plane systolic excursion, demonstrating a positive effect on RV pressure overload and systolic function.In vitro findings support these results.Macrophages and PASMCs exposed to AGEs or hypoxia showed increased levels of AGEs, HMGB1, S100β, and RAGE, all of which were reduced by PM.Notably, hypoxiaconditioned PASMC medium enhanced RAGE signaling in macrophages, highlighting intercellular cross-talk through RAGE ligands.Unlike direct RAGE antagonists, which may disrupt normal immune signaling, PM acts upstream by blocking AGE formation and