青蒿琥酯通过miR-16-5p和TXNIP对NLRP3炎性小体的调控作用对动脉粥样硬化的抗炎作用
Anti-inflammatory effects of artesunate on atherosclerosis via miR-16-5p and TXNIP regulation of the NLRP3 inflammasome.
作者信息
Li Bo, Zhang Zheqi, Fu Yili
机构信息
School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Department of Endocrinology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
出版信息
Ann Transl Med. 2021 Oct;9(20):1558. doi: 10.21037/atm-21-4939.
BACKGROUND
Atherosclerosis (AS) is chronic inflammatory arterial disorder. Artesunate could exhibit anti-inflammatory activity in AS, but its role in AS is still in its incipient stage. In this study, we explored the anti-inflammatory effect of artesunate in AS and its underlying mechanism.
METHODS
We isolated CD14 monocytes from peripheral blood (PB) of 115 coronary heart disease (CHD) patients and 33 non-CHD patients confirmed by coronary angiography. Phorbol myristate acetate (PMA) was used to induce the differentiation of THP-1 monocytes to macrophages. Cells were treated with artesunate at a final concentration of 2.5, 5 or 10 µmol/L. The activation of NLRP3 inflammasome was assessed by immunoblotting of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The expression of pro-caspase-1/pro-interleukin (IL)-1β/pro-IL-18 and their mature forms was measured using immunoblotting. A rat model of AS was induced by vitamin D3 (VD3) and a 21-day high-fat diet.
RESULTS
Downregulated miR-16-5p and upregulated thioredoxin-interacting protein (TXNIP) was determined in CD14 monocytes from CHD patients and associated with disease severity. Artesunate abrogated the activation of NLRP3 inflammasome in the presence of inflammasome activators in cultured macrophages. Artesunate reduced TXNIP expression and impaired the interaction between TXNIP and NLRP3, thereby inhibiting release of inflammatory cytokines and ASC production in cultured macrophages. In addition, miR-16-5p negatively regulated the messenger RNA (mRNA) of TXNIP. Artesunate increased the expression of miR-16-5p in a dose-dependent manner, and inhibition of miR-16-5p enhanced the secretion of inflammatory cytokines. Our experiments also demonstrated that artesunate reduced lipid accumulation, atherosclerotic plaque formation, and antagonized inflammation in a dose-dependent manner by upregulating miR-16-5p.
CONCLUSIONS
In summary, the present study unveiled a mechanism underlying the anti-inflammatory role of artesunate in AS.
背景
动脉粥样硬化（AS）是一种慢性炎症性动脉疾病。青蒿琥酯在AS中可表现出抗炎活性，但其在AS中的作用仍处于初始阶段。在本研究中，我们探讨了青蒿琥酯在AS中的抗炎作用及其潜在机制。
方法
我们从115例经冠状动脉造影确诊的冠心病（CHD）患者和33例非CHD患者的外周血（PB）中分离出CD14单核细胞。用佛波酯（PMA）诱导THP-1单核细胞分化为巨噬细胞。细胞用终浓度为2.5、5或10μmol/L的青蒿琥酯处理。通过对含半胱天冬酶募集结构域的凋亡相关斑点样蛋白（ASC）进行免疫印迹来评估NLRP3炎性小体的激活。使用免疫印迹法检测前半胱天冬酶-1/前白细胞介素（IL）-1β/前IL-18及其成熟形式的表达。用维生素D3（VD3）和21天高脂饮食诱导AS大鼠模型。
结果
在CHD患者的CD14单核细胞中检测到miR-16-5p下调和硫氧还蛋白相互作用蛋白（TXNIP）上调，且与疾病严重程度相关。在培养的巨噬细胞中，青蒿琥酯在炎性小体激活剂存在的情况下消除了NLRP3炎性小体的激活。青蒿琥酯降低TXNIP表达并削弱TXNIP与NLRP3之间的相互作用，从而抑制培养的巨噬细胞中炎性细胞因子的释放和ASC的产生。此外，miR-16-5p负调控TXNIP的信使核糖核酸（mRNA）。青蒿琥酯以剂量依赖的方式增加miR-16-5p的表达，抑制miR-16-5p可增强炎性细胞因子的分泌。我们的实验还表明，青蒿琥酯通过上调miR-16-5p以剂量依赖的方式减少脂质积累、动脉粥样硬化斑块形成并拮抗炎症。
结论
总之，本研究揭示了青蒿琥酯在AS中抗炎作用的潜在机制。
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