Archives of medical research · 2025
Intracellular Galectin-3 as a Crucial Regulator of Foam Cell Formation and Apoptosis Progression Through the Modulation of Membrane Lipid Rafts.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Liu Wen-Cheng, Lin Chin-Sheng, Luo Chen-Ling, Yang Weng-Yu, Yang Cheng-Hung, Cheng Mei-Ling, Tsai Min-Chien, Lin Wei-Shiang, Shui Hao-Ai, Chuang Yi-Ping
Аннотация
BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease (CVD) mortality worldwide, is characterized by dysregulated lipid metabolism and unresolved inflammation. Macrophage-derived foam cell formation and apoptosis contribute to plaque formation and vulnerability. Elevated serum galectin-3 (Gal-3) levels are associated with increased CVD risk, and Gal-3 in plaques is strongly associated with macrophages. However, its impact on inflammation remains controversial.
METHODS: An in vitro model using human THP-1-derived macrophages was established to simulate inflammatory foam cells. CRISPR-Cas9-assisted LGALS3 knockout in THP-1 cells was performed to elucidate the functional role of Gal-3 in inflammation and apoptosis.
RESULTS: OxLDL-internalized THP-1-derived foam cells secreted significant Gal-3 upon lipopolysaccharide (LPS) treatment, mimicking elevated Gal-3 levels observed in patients with CVD. LPS-treated foam cells showed Gal-3-dependent inflammation, endoplasmic reticulum stress, and apoptosis progression. LGALS3 knockout reduced oxLDL uptake and inflammation, accompanied by decreased surface expression of CD36 and CD14. This indicates a disrupted lipid raft structure, as confirmed by reduced cholera toxin B subunit recognition and altered sphingolipid profile. Gal-3 inhibitors GB1107 and TD139 attenuated LPS-induced cytokine production. Notably, only GB1107 inhibited oxLDL uptake by partially disrupting lipid raft organization, due to its superior membrane permeability. GB1107 further altered Gal-3 nuclear localization under LPS or oxLDL exposure, suggesting a potential nuclear role during inflammation. Importantly, GB1107 reduced foam cell formation in primary human monocyte-derived macrophages, supporting its translational relevance.
CONCLUSIONS: Gal-3 modulates lipid raft organization and oxLDL internalization, acting as a pro-inflammatory mediator in foam cell biology. These findings highlight Gal-3 as a potential therapeutic target for early atherosclerosis.
METHODS: An in vitro model using human THP-1-derived macrophages was established to simulate inflammatory foam cells. CRISPR-Cas9-assisted LGALS3 knockout in THP-1 cells was performed to elucidate the functional role of Gal-3 in inflammation and apoptosis.
RESULTS: OxLDL-internalized THP-1-derived foam cells secreted significant Gal-3 upon lipopolysaccharide (LPS) treatment, mimicking elevated Gal-3 levels observed in patients with CVD. LPS-treated foam cells showed Gal-3-dependent inflammation, endoplasmic reticulum stress, and apoptosis progression. LGALS3 knockout reduced oxLDL uptake and inflammation, accompanied by decreased surface expression of CD36 and CD14. This indicates a disrupted lipid raft structure, as confirmed by reduced cholera toxin B subunit recognition and altered sphingolipid profile. Gal-3 inhibitors GB1107 and TD139 attenuated LPS-induced cytokine production. Notably, only GB1107 inhibited oxLDL uptake by partially disrupting lipid raft organization, due to its superior membrane permeability. GB1107 further altered Gal-3 nuclear localization under LPS or oxLDL exposure, suggesting a potential nuclear role during inflammation. Importantly, GB1107 reduced foam cell formation in primary human monocyte-derived macrophages, supporting its translational relevance.
CONCLUSIONS: Gal-3 modulates lipid raft organization and oxLDL internalization, acting as a pro-inflammatory mediator in foam cell biology. These findings highlight Gal-3 as a potential therapeutic target for early atherosclerosis.