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<p>Atherosclerosis is mediated by circulating monocytes and lesional macrophages through chronic inflammation accompanied by metabolic reprogramming. Although methionine metabolism enhances the proinflammatory capacity of monocytes/macrophages, its role in atherosclerosis remains unclear. Here, we use untargeted metabolomics and mass spectrometry to demonstrate that monocyte methionine metabolism is associated with vulnerable plaque (thin-cap fibroatheroma [TCFA]) identified by pancoronary optical coherence tomography. Methionine adenosyltransferase Ⅱ alpha (MAT2A), the key enzyme of methionine metabolism, is highly expressed in atherosclerosis. Further epigenetic profiling of inflammatory and migratory gene promoters reveals MAT2A-mediated enrichment of the transcriptional permissive chromatin mark H3K4me3. Myeloid-specific MAT2A ablation and pharmacological inhibition, or a low-methionine diet, reduce monocyte/macrophage inflammation and migration, thereby attenuating plaque vulnerability. Mechanistically, norepinephrine activates the mTOR-c-MYC axis to upregulate MAT2A expression. The combination of norepinephrine and methionine metabolism is associated with TCFA presence and 5-year clinical prognosis. Consequently, MAT2A-mediated methionine metabolism represents a potential therapeutic target for atherosclerosis.</p>

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MAT2A promotes atherosclerotic plaque vulnerability by mediating epigenetic reprogramming of macrophages

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月16日

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  • Zhuo Du,
  • Pingping Wan,
  • Manyu Du,
  • Song Li,
  • Qiuying Yan,
  • Sibo Sun,
  • Caiying Tang,
  • Ziquan Jiang,
  • Shuang Li,
  • Guoxia Shi,
  • Baixue Miao,
  • Xiaoyu Du,
  • Shilong Li,
  • Shaohong Fang,
  • Chao Wang,
  • Chao Fang,
  • Bo Yu,
  • Jiannan Dai,
  • Ping Sun

摘要

Atherosclerosis is mediated by circulating monocytes and lesional macrophages through chronic inflammation accompanied by metabolic reprogramming. Although methionine metabolism enhances the proinflammatory capacity of monocytes/macrophages, its role in atherosclerosis remains unclear. Here, we use untargeted metabolomics and mass spectrometry to demonstrate that monocyte methionine metabolism is associated with vulnerable plaque (thin-cap fibroatheroma [TCFA]) identified by pancoronary optical coherence tomography. Methionine adenosyltransferase Ⅱ alpha (MAT2A), the key enzyme of methionine metabolism, is highly expressed in atherosclerosis. Further epigenetic profiling of inflammatory and migratory gene promoters reveals MAT2A-mediated enrichment of the transcriptional permissive chromatin mark H3K4me3. Myeloid-specific MAT2A ablation and pharmacological inhibition, or a low-methionine diet, reduce monocyte/macrophage inflammation and migration, thereby attenuating plaque vulnerability. Mechanistically, norepinephrine activates the mTOR-c-MYC axis to upregulate MAT2A expression. The combination of norepinephrine and methionine metabolism is associated with TCFA presence and 5-year clinical prognosis. Consequently, MAT2A-mediated methionine metabolism represents a potential therapeutic target for atherosclerosis.