Department of Cardiology, The 2nd affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China.
National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, People's Republic of China.
Mol Med. 2023 Jun 12;29(1):73. doi: 10.1186/s10020-023-00656-z.
Elevated plasma homocysteine levels, known as hyperhomocysteinemia, have been identified as an independent risk factor for atherosclerosis and related cardiovascular diseases. Macrophage pyroptosis-mediated inflammation is crucial in the development of atherosclerosis, but the underlying mechanisms remain unclear.
A hyperhomocysteinemia atherosclerotic model with ApoE mice fed with a high-methionine diet was constructed to investigate the role of plasma homocysteine in atherosclerosis. THP-1-derived macrophages were used to investigate the mechanisms by which Hcy regulates pyroptosis.
We found that hyperhomocysteinemia resulted in larger atherosclerotic plaques and more secretion of inflammatory cytokines, while these effects were attenuated in Caspase-1 knockdown mice. Likewise, in vitro experiments demonstrated that treatment of macrophages with homocysteine resulted in NLRP3 inflammasome activation and pyroptosis, as evidenced by cleavage of Caspase-1, production of downstream IL-1β, elevation of lactate dehydrogenase activity, and extensive propidium iodide-positive staining of cells. These were all inhibited by Caspase-1 inhibitor. In addition, excessive generation of reactive oxygen species was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential and ATP synthesis. Moreover, further experiments revealed that homocysteine induced endoplasmic reticulum stress, enhanced communication between the endoplasmic reticulum and mitochondria, and consequently contributed to calcium disorder. Furthermore, the endoplasmic reticulum stress inhibitor, 4PBA, the calcium chelator, BAPTA, and calcium channel inhibitor, 2-APB significantly improved macrophage pyroptosis.
Homocysteine accelerates atherosclerosis progression by enhancing macrophages pyroptosis via promoting endoplasmic reticulum stress, endoplasmic reticulum-mitochondria coupling, and disturbing of calcium disorder.
血浆同型半胱氨酸水平升高，即高同型半胱氨酸血症，已被确定为动脉粥样硬化和相关心血管疾病的独立危险因素。巨噬细胞焦亡介导的炎症在动脉粥样硬化的发生发展中起关键作用，但具体机制尚不清楚。
构建了载脂蛋白 E 敲除（ApoE-/-）小鼠高蛋氨酸饮食诱导的高同型半胱氨酸血症动脉粥样硬化模型，以研究血浆同型半胱氨酸在动脉粥样硬化中的作用。用 THP-1 源性巨噬细胞研究同型半胱氨酸调节焦亡的机制。
我们发现高同型半胱氨酸血症导致动脉粥样硬化斑块增大，炎症细胞因子分泌增多，而 Caspase-1 敲低小鼠的这些作用减弱。同样，体外实验表明，同型半胱氨酸处理巨噬细胞导致 NLRP3 炎性小体激活和焦亡，表现为 Caspase-1 裂解、下游白细胞介素-1β（IL-1β）产生、乳酸脱氢酶活性升高以及碘化丙啶阳性染色的细胞广泛增加，这些作用均可被 Caspase-1 抑制剂抑制。此外，过量的活性氧生成与线粒体功能障碍有关，表现为线粒体膜电位丧失和 ATP 合成减少。此外，进一步的实验表明，同型半胱氨酸诱导内质网应激，增强内质网和线粒体之间的通讯，进而导致钙紊乱。此外，内质网应激抑制剂 4-己基间苯二酚（4PBA）、钙螯合剂 BAPTA 和钙通道抑制剂 2-APB 显著改善了巨噬细胞焦亡。
同型半胱氨酸通过促进内质网应激、内质网-线粒体偶联以及扰乱钙紊乱，增强巨噬细胞焦亡，从而加速动脉粥样硬化的进展。
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