Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation
Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation
复制标题
可溶性尿酸通过AMPK（AMP活化蛋白激酶）介导的炎症促进动脉粥样硬化
DOI：
10.1161/atvbaha.119.313224
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发表时间：
2020-03-01
影响因子：
8.7
通讯作者：
Kono, Hajime
中科院分区：
文献类型：
--
作者：
Kimura, Yoshitaka;Yanagida, Tamiko;Kono, Hajime
目的：尿酸被认为与动脉粥样硬化有关，但尚未确定。尿酸从受损的细胞中释放出来，形成尿酸盐晶体，被免疫系统识别并产生IL(白介素1)。危险信号和IL-1已被证明在动脉粥样硬化中起重要作用。方法与结果：血清尿酸生理水平可促进NLRP3(Nacht、LRR和PYD结构域含蛋白3)介导的炎症体分泌IL-1β。这种炎症的增强是通过调节AMPK(AMP激活的蛋白激酶)-mTOR(哺乳动物雷帕霉素的靶标)线粒体活性氧物种和HIF-1α(缺氧诱导因子-1α)途径来实现的。在尿酸酶转基因和黄嘌呤氧化酶抑制剂处理的小鼠中，尿酸水平的降低导致AMPK的激活和动脉粥样硬化斑块的发展减弱。此外，健康人服用苯溴马龙2周后，急性血尿酸水平显著降低，血浆IL-18水平显著降低。结论：尿酸在体内促进了动脉粥样硬化和炎症的发展。此外，尿酸水平的降低通过激活AMPK途径来减轻炎症。这项研究提供了降尿酸治疗动脉粥样硬化的机制证据。
Objective:Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis.Approach and Results:The secretion of IL-1 beta from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway. In both of uricase transgenic and xanthine oxidase inhibitor-treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18-an inflammasome-dependent cytokine.Conclusions:The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.