Division of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Mediators Inflamm. 2022 Sep 21;2022:5463505. doi: 10.1155/2022/5463505. eCollection 2022.
Long non-coding RNAs (lncRNAs) play many important roles in gene regulation and disease pathogenesis. Here, we sought to determine that mitochondrial dynamic related lncRNA (MDRL) modulates NLRP3 inflammasome activation and apoptosis of vascular smooth muscle cells (VSMCs) and protects arteries against atherosclerosis.
experiments, we applied LDLR knockout (LDLR) mice fed the high-fat diet to investigate the effects of MDRL on atherosclerosis. experiments, we applied mouse aortic smooth muscle cells to determine the mechanism of MDRL in abrogating NLRP3 inflammasome and inhibiting cell apoptosis through miR-361/sequentosome 1 (SQSTM1) by TUNEL staining, quantitative RT-PCR, western blot, microribonucleoprotein immunoprecipitation, and luciferase reporter assay.
Downregulated MDRL and increased NLRP3 were observed in mouse atherosclerotic plaques, accompanied with the increase of miR-361. The results showed that MDRL overexpression significantly attenuated the burden of atherosclerotic plaque and facilitated plaque stability through inhibiting NLRP3 inflammasome activation and cell apoptosis, and vice versa. Mechanically, MDRL suppressed NLRP3 inflammasome activation and VSMC apoptosis via suppressing miR-361. Furthermore, miR-361 directly bound to the 3'UTR of SQSTM1 and inhibited its translation, subsequently activating NLRP3 inflammasome. Systematic delivery of miR-361 partly counteracted the beneficial effects of MDRL overexpression on atherosclerotic development in LDLR mice.
In summary, MDRL alleviates NLRP3 inflammasome activation and apoptosis in VSMCs through miR-361/SQSTM1/NLRP3 pathway during atherogenesis. These data indicate that MDRL and inhibition of miR-361 represent potential therapeutic targets in atherosclerosis-related diseases.
长链非编码 RNA（lncRNA）在基因调控和疾病发病机制中发挥着许多重要作用。在这里，我们试图确定线粒体动态相关 lncRNA（MDRL）是否调节 NLRP3 炎性体激活和血管平滑肌细胞（VSMC）凋亡，并保护动脉免受动脉粥样硬化的影响。
在实验中，我们应用 LDLR 敲除（LDLR）小鼠喂食高脂肪饮食来研究 MDRL 对动脉粥样硬化的影响。在实验中，我们应用小鼠主动脉平滑肌细胞来确定 MDRL 通过 TUNEL 染色、定量 RT-PCR、western blot、微核糖核蛋白免疫沉淀和荧光素酶报告基因分析来破坏 NLRP3 炎性体并抑制细胞凋亡的机制。
在小鼠动脉粥样硬化斑块中观察到下调的 MDRL 和增加的 NLRP3，同时伴随着 miR-361 的增加。结果表明，MDRL 过表达通过抑制 NLRP3 炎性体激活和细胞凋亡，显著减轻动脉粥样硬化斑块的负担并促进斑块稳定，反之亦然。从机制上讲，MDRL 通过抑制 miR-361 来抑制 NLRP3 炎性体激活和 VSMC 凋亡。此外，miR-361 直接结合 SQSTM1 的 3'UTR 并抑制其翻译，从而激活 NLRP3 炎性体。系统递送 miR-361 部分抵消了 MDRL 过表达对 LDLR 小鼠动脉粥样硬化发展的有益影响。
总之，在动脉粥样硬化发生过程中，MDRL 通过 miR-361/SQSTM1/NLRP3 通路减轻 VSMC 中的 NLRP3 炎性体激活和凋亡。这些数据表明，MDRL 和抑制 miR-361 可能成为与动脉粥样硬化相关疾病的潜在治疗靶点。
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