Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis.
Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis.
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受体相互作用蛋白激酶 3 抑制可通过维持线粒体稳态来防止镉介导的巨噬细胞极化和随后的动脉粥样硬化
DOI：
10.3389/fcvm.2021.737652
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发表时间：
2021
影响因子：
3.6
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Zhang J;Feng W;Li M;Chen P;Ning X;Ou C;Chen M
慢性镉暴露可导致心血管疾病，尤其是动脉粥样硬化的发生发展，但其机制尚不清楚。由于线粒体内环境稳定正在成为CVD发展的核心参与者，因此它可能是连接镉暴露和AS的潜在机制。本研究旨在通过巨噬细胞极化研究镉介导的动脉粥样硬化，了解镉引起线粒体稳态失衡的机制。流式细胞仪检测结果显示，镉暴露可促进巨噬细胞M1型极化，表现为活化B的核因子κ轻链增强子（NF-κ B）和NLR家族pyrin domain containing 3（NLRP 3）的表达增加。线粒体内稳态检测显示，线粒体膜电位和噬菌体的降低、线粒体超氧化物（mROS）的增加以及线粒体的分裂参与了镉诱导的巨噬细胞极化。受体相互作用蛋白激酶3（RIPK 3）和假激酶混合谱系激酶结构域样蛋白（p-MLKL）表达上调。敲除RIPK 3，随后降低p-MLKL的表达，改善了线粒体稳态失衡，这有效地逆转了巨噬细胞极化。在体内，油红O染色显示，高血镉显著加重AS。免疫荧光和western blot检测发现，小鼠主动脉根部存在M1型巨噬细胞极化和线粒体稳态失衡。敲除RIPK 3恢复了上述变化。最后，给予N-乙酰半胱氨酸（NAC）或线粒体分裂抑制剂-1（Mdivi-1），减少mROS或线粒体分裂，抑制RIPK 3和p-MLKL的表达，减弱镉处理组中的AS和巨噬细胞M1型极化。因此，镉暴露激活了RIPK 3通路，损害了线粒体的稳态，导致促炎性巨噬细胞极化和随后的AS。敲除RIPK 3为镉引起的巨噬细胞极化和随后的AS提供了潜在的治疗靶点。
Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.
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DOI：
10.1136/bmj.k3310
发表时间：
2018-08-29
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Chowdhury R;Ramond A;O'Keeffe LM;Shahzad S;Kunutsor SK;Muka T;Gregson J;Willeit P;Warnakula S;Khan H;Chowdhury S;Gobin R;Franco OH;Di Angelantonio E
通讯作者：
Di Angelantonio E
影响因子：
3.9
作者：
Chen, Xiao;Zhu, Guoying;Gu, Shuzhu
通讯作者：
Gu, Shuzhu
影响因子：
3.5
作者：
Ninkov, Marina;Aleksandrov, Aleksandra Popov;Kataranovski, Milena
通讯作者：
Kataranovski, Milena
DOI：
10.1152/ajplung.00184.2003
发表时间：
2004-11-01
影响因子：
4.9
作者：
Wirth, D;Bureau, F;Gustin, P
通讯作者：
Gustin, P
DOI：
10.1161/atvbaha.109.190082
发表时间：
2009-09-01
影响因子：
8.7
作者：
Messner, Barbara;Knoflach, Michael;Bernhard, David
通讯作者：
Bernhard, David