Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition.
Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition.
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褪黑激素通过线粒体自噬激活和 NLRP3 炎症小体抑制改善动脉粥样硬化的进展
DOI：
10.1155/2018/9286458
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发表时间：
2018
影响因子：
--
通讯作者：
Cao F
中科院分区：
文献类型：
--
作者：
Ma S;Chen J;Feng J;Zhang R;Fan M;Han D;Li X;Li C;Ren J;Wang Y;Cao F
NLRP 3（nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3）炎性小体介导的炎症反应与动脉粥样硬化（atherosclerosis，AS）的发生发展密切相关，AS是心血管疾病的重要病因。褪黑激素具有抗炎作用。然而，褪黑激素在AS病理过程中的潜在作用知之甚少。在此，我们证明褪黑激素通过巨噬细胞线粒体自噬清除活性氧（ROS）抑制动脉粥样硬化病变中NLRP 3炎性小体的长期激活。使用ApoE−/−小鼠通过高脂饮食诱导动脉粥样硬化小鼠模型。褪黑激素治疗显着衰减AS斑块的大小和脆弱性。此外，褪黑激素减少NLRP 3炎性小体激活和随后的IL-1β分泌在动脉粥样硬化病变。尽管蛋白质表达不变，沉默的信息调节因子3（Sirt 3）的活性升高，在褪黑激素治疗的小鼠动脉粥样硬化病变。在ox-LDL处理的巨噬细胞中，褪黑激素减弱了NLRP 3炎性体激活和炎性因子分泌，而这种保护作用被Sirt 3沉默或自噬抑制剂3-MA所消除。线粒体活性氧（mitoROS），这是一个公认的诱导剂NLRP 3炎性小体，通过诱导线粒体吞噬褪黑素减弱。Sirt 3-siRNA和自噬抑制剂3-MA都部分消除了褪黑激素对线粒体ROS清除和NLRP 3炎性小体激活的有益作用，表明Sirt 3介导的线粒体自噬的关键作用。此外，我们证明褪黑激素通过Sirt 3/FOXO 3a/Parkin信号通路保护AS。总之，目前的研究表明，褪黑激素预防动脉粥样硬化进展，至少部分，通过诱导线粒体自噬和减弱NLRP 3炎性小体激活，这是由Sirt 3/FOXO 3a/Parkin信号通路介导的。总的来说，我们的研究为褪黑激素作为AS治疗干预的新靶点提供了见解。
The NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti-inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high-fat diet using ApoE−/− mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL-1β secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin-treated mice. In ox-LDL-treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3-MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3-siRNA and autophagy inhibitor 3-MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3-mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.
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影响因子：
4.8
作者：
Li, NY;Ragheb, K;Robinson, JP
通讯作者：
Robinson, JP
影响因子：
13.3
作者：
Pi H;Xu S;Reiter RJ;Guo P;Zhang L;Li Y;Li M;Cao Z;Tian L;Xie J;Zhang R;He M;Lu Y;Liu C;Duan W;Yu Z;Zhou Z
通讯作者：
Zhou Z
影响因子：
33.6
作者：
Nogueiras R;Habegger KM;Chaudhary N;Finan B;Banks AS;Dietrich MO;Horvath TL;Sinclair DA;Pfluger PT;Tschöp MH
通讯作者：
Tschöp MH
影响因子：
5.6
作者：
Huang, LS;Cobessi, D;Berry, EA
通讯作者：
Berry, EA
影响因子：
6
作者：
Jin HS;Suh HW;Kim SJ;Jo EK
通讯作者：
Jo EK