Anti-malarial artesunate ameliorates atherosclerosis by modulating arterial inflammatory responses via inhibiting the NF-κB-NLRP3 inflammasome pathway.
Anti-malarial artesunate ameliorates atherosclerosis by modulating arterial inflammatory responses via inhibiting the NF-κB-NLRP3 inflammasome pathway.
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抗疟疾青蒿酯通过抑制 NF-κB -NLRP3 炎症小体途径调节动脉炎症反应，从而改善动脉粥样硬化
DOI：
10.3389/fphar.2023.1123700
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
慢性炎症在动脉粥样硬化（AS）的发病机制中起着关键作用，涉及血液成分、巨噬细胞和动脉壁之间复杂的相互作用。因此，开发针对AS的靶向治疗是有价值的。方法：采用致动脉粥样硬化饮食加脂多糖（LPS）诱导AS大鼠模型，然后用青蒿素琥珀酸衍生物抗疟青蒿琥酯（Art）治疗。采用油红O、苏木精-伊红、马松染色观察动脉形态。采用免疫组化或免疫荧光法检测动脉蛋白水平。采用PCR阵列或real-time PCR检测mRNA表达水平。结果：我们发现Art对AS大鼠具有剂量依赖性的保护作用。Art对动脉斑块和血脂的抑制作用与瑞舒伐他汀（RS）相当，对动脉脂质沉积和由动脉壁增厚和血管胶原沉积组成的动脉重塑的抑制作用也优于RS。Art对AS大鼠的改善与抑制动脉巨噬细胞募集、抑制核因子κB （NF-κB）相关的过度动脉炎症反应有关。重要的是，Art通过下调nod样受体热蛋白结构域相关蛋白3 （NLRP3）和凋亡相关斑点样蛋白含有CARD （ASC）的表达，显著抑制动脉壁和动脉巨噬细胞中NLRP3炎性小体的激活，导致AS大鼠NLRP3炎性小体衍生的caspase-1、白细胞介素-1β (IL-1β)、IL-18以及随后的转化生长因子β1 （TGF-β1）的产生减少。结论：我们认为Art是一种抗as药物，通过抑制NF-κ b - NLRP3炎症小体通路来调节动脉炎症反应。
Introduction: Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis (AS), and involves a complex interplay between blood components, macrophages, and arterial wall. Therefore, it is valuable in the development of targeted therapies to treat AS. Methods: AS rat model was induced by atherogenic diet plus with lipopolysaccharide (LPS) and then treated by anti-malarial artesunate (Art), a succinate derivative of artemisinin. The arterial morphology was observed after Oil red O, hematoxylin—eosin, and Masson’s staining. The arterial protein level was detected by immunohistochemistry or immunofluorescence. The expression level of mRNA was determined by PCR array or real-time PCR. Results: Herein, we showed that Art possessed a dose-dependently protective effect on AS rats. In detail, Art showed a comparable inhibitory effect on arterial plaque and serum lipids compared to those of rosuvastatin (RS), and further showed a better inhibition on arterial lipid deposition and arterial remodeling comprised of arterial wall thicken and vascular collagen deposition, than those of RS. The improvement of Art on AS rats was related to inhibit arterial macrophage recruitment, and inhibit nuclear factor κB (NF-κB)-related excessive arterial inflammatory responses. Critically, Art showed significant inhibition on the NLRP3 inflammasome activation in both arterial wall and arterial macrophages, by down-regulating the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and apoptosis associated speckle-like protein containing CARD (ASC), leading to less production of the NLRP3 inflammasome—derived caspase-1, interleukin-1β (IL-1β), IL-18, and subsequent transforming growth factor β1 (TGF-β1) in AS rats. Conclusion: We propose that Art is an anti-AS agent acts through modulating the arterial inflammatory responses via inhibiting the NF-κB – NLRP3 inflammasome pathway.