Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Dec;1869(8):159559. doi: 10.1016/j.bbalip.2024.159559. Epub 2024 Aug 22.
Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal flora, is recognized as an independent risk factor for atherosclerosis and atherosclerotic cardiovascular diseases. However, the underlying mechanism remains poorly understood. Here, we showed that dietary TMAO supplementation accelerates atherosclerosis in ApoE mice. Pyroptosis and the expression of phospholipid-modifying enzyme MBOAT2 were increased in endothelial cells within atherosclerotic lesions. Genetic upregulation of MBOAT2 via adeno-associated virus with endothelium-specific promoter results in increased atherosclerotic lesions in ApoE mice. Mechanistically, the overexpression of MBOAT2 disrupted glycerophospholipid metabolism and induced endothelial cell pyroptosis in an Endoplasmic reticulum stress-dependent manner. These data reveal that TMAO promotes endothelial cell pyroptosis and the progression of atherosclerotic lesions through the upregulation of MBOAT2, indicating that MBOAT2 is a promising therapeutic target for atherosclerosis.
三甲胺 N-氧化物（TMAO）是肠道菌群产生的一种代谢物，被认为是动脉粥样硬化和动脉粥样硬化性心血管疾病的独立危险因素。然而，其潜在机制仍知之甚少。在这里，我们表明膳食 TMAO 补充加速了 ApoE 小鼠的动脉粥样硬化。在动脉粥样硬化病变中的内皮细胞中，细胞焦亡和磷脂修饰酶 MBOAT2 的表达增加。通过带有内皮细胞特异性启动子的腺相关病毒对 MBOAT2 的基因上调导致 ApoE 小鼠的动脉粥样硬化病变增加。在机制上，MBOAT2 的过表达通过内质网应激依赖性方式破坏甘油磷脂代谢并诱导内皮细胞细胞焦亡。这些数据表明，TMAO 通过上调 MBOAT2 促进内皮细胞细胞焦亡和动脉粥样硬化病变的进展，表明 MBOAT2 是动脉粥样硬化的一个有前途的治疗靶点。
