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bioRxiv · 10.1101/2024.12.12.628145

Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes

Mosalmanzadeh, N.·Maurmann, R. M.·Davis, K.·Schmitt, B. L.·Makowski, L.·Pence, B. D.
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Abstract

Atherosclerosis, a major contributor to cardiovascular disease, involves lipid accumulation and inflammatory processes in arterial walls, with oxidized low-density lipoprotein (OxLDL) playing a central role. OxLDL is increased during aging and stimulates monocyte transformation into foam cells and induces metabolic reprogramming and pro-inflammatory responses, accelerating atherosclerosis progression and contributing to other age-related diseases. This study investigated the effects of Mdivi-1, a mitochondrial fission inhibitor, and S1QEL, a selective complex I-associated reactive oxygen species (ROS) inhibitor, on OxLDL-induced responses in monocytes. Healthy monocytes isolated from participants were treated with OxLDL, with or without Mdivi-1 or S1QEL, and assessed for metabolic shifts, inflammatory cytokine expression, foam cell formation, and ROS production. OxLDL treatment elevated glycolytic activity (ECAR) and expression of pro-inflammatory cytokines IL1B and CXCL8, promoting foam cell formation and mitochondrial ROS (mtROS) production. Mdivi-1 and S1QEL effectively reduced OxLDL-induced glycolytic reprogramming, inflammatory cytokine levels, and foam cell formation while limiting mtROS. These findings suggest that both Mdivi-1 and S1QEL modulate key monocyte responses to OxLDL, providing insights into potential therapeutic approaches for age-related diseases.

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Mosalmanzadeh, N., Maurmann, R. M., Davis, K., Schmitt, B. L., Makowski, L., Pence, B. D.. 2024-12-17. Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes. https://doi.org/10.1101/2024.12.12.628145

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