Novel Role for Tranilast in Regulating NLRP3 Ubiquitination, Vascular Inflammation, and Atherosclerosis
Novel Role for Tranilast in Regulating NLRP3 Ubiquitination, Vascular Inflammation, and Atherosclerosis
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曲尼司特在调节 NLRP3 泛素化、血管炎症和动脉粥样硬化中的新作用
DOI：
10.1161/jaha.119.015513
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发表时间：
2020-06-16
影响因子：
5.4
通讯作者：
Fu, Jian
中科院分区：
文献类型：
--
作者：
Chen, Suwen;Wang, Yadong;Fu, Jian
背景：炎症小体NLRP3(核苷酸结合寡聚区，富含亮氨酸重复序列的受体家族，含3)的异常激活被认为在动脉粥样硬化中起到致病作用。NLRP3保持在不活跃的泛素化状态，以避免不必要的NLRP3炎症体激活。本研究旨在验证NLRP3泛素化的药物操作可以钝化NLRP3炎症体的组装和激活，并保护血管炎症和动脉粥样硬化的假说。由于遗传学研究在低密度脂蛋白受体或载脂蛋白E缺陷小鼠的动脉粥样硬化中的作用有不同的结果，这项研究试图澄清使用这两种模型的药理学方法的差异。方法和结果：我们提供了第一个证据表明曲尼司特促进NLRP3泛素化。我们发现曲尼司特抑制了NLRP3的齐聚，并抑制了NLRP3炎性小体的组装。曲尼司特显著抑制低密度脂蛋白受体和载脂蛋白E缺乏的巨噬细胞中NLRP3炎症体的激活。通过重组人胚胎肾293T细胞中的NLRP3炎症体，我们发现曲尼司特直接限制了NLRP3炎症体的激活。通过采用不同方案的曲尼司特治疗低密度脂蛋白受体和载脂蛋白E缺陷小鼠，我们证明曲尼司特可以钝化动脉粥样硬化的发生和发展。与对照组相比，接受曲尼司特治疗的小鼠动脉粥样硬化病变面积显著缩小，同时巨噬细胞含量和斑块中炎症分子的表达显著下降。结论：曲尼司特能有效增强NLRP3泛素化，钝化NLRP3炎症小体的组装和激活，改善低密度脂蛋白受体和载脂蛋白E缺陷小鼠的血管炎症和动脉粥样硬化。
BACKGROUND: Aberrant activation of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP3 ubiquitination blunts the assembly and activation of the NLRP3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low-density lipoprotein receptor- or apolipoprotein E-deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models.METHODS AND RESULTS: We provided the first evidence demonstrating that tranilast facilitates NLRP3 ubiquitination. We showed that tranilast restricted NLRP3 oligomerization and inhibited NLRP3 inflammasome assembly. Tranilast markedly suppressed NLRP3 inflammasome activation in low-density lipoprotein receptor- and apolipoprotein E-deficient macrophages. Through reconstitution of the NLRP3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP3 inflammasome activation. By adopting different regimens for tranilast treatment of low-density lipoprotein receptor- and apolipoprotein E-deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP3 inflammasome in the atherosclerotic lesions.CONCLUSIONS: Tranilast potently enhances NLRP3 ubiquitination, blunts the assembly and activation of the NLRP3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low-density lipoprotein receptor- and apolipoprotein E-deficient mice.