Int Immunopharmacol. 2025 Dec 12;169:116019. doi: 10.1016/j.intimp.2025.116019. Online ahead of print.
ABSTRACT
BACKGROUND: Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis.
METHODS: The ApoE-/- mice were fed a 16-week high-fat diet (HFD). 16 weeks were spent on melatonin therapy. After using 3-TYP to suppress Sirt3 function, we were able to measure the vascular tissue’s biochemical, inflammatory, and mitochondrial fission characteristics as well as the shape of atherosclerotic plaque. RAW264.7 cells were stimulated by oxidized low-density lipoprotein (oxLDL), pretreated with or without 3-TYP or Melatonin.
RESULTS: The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of Sirt3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, Sirt3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated Sirt3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the other hand, melatonin’s inhibitory effects on Drp1 expression and mitochondrial fission were lessened by Sirt3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL.
CONCLUSION: Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin’s suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients.
PMID:41389666 | DOI:10.1016/j.intimp.2025.116019