Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia.
Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia.
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DOI：
10.1016/j.jlr.2022.100298
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发表时间：
2022-12
影响因子：
6.5
通讯作者：
Li, Pin-Lan
中科院分区：
文献类型：
--
作者：
Yuan, Xinxu;Bhat, Owais M.;Zou, Yao;Li, Xiang;Zhang, Yang;Li, Pin-Lan
关键词：
NOD 样受体热蛋白结构域 3 (NLRP3) 炎症小体在动脉粥样硬化形成过程中被激活，但其如何发生尚不清楚。在这里，我们探索了通过酸性鞘磷脂酶（ASM）-神经酰胺信号通路激活和调节 NLRP3 炎症小体的机制。作为新内膜形成模型，对内皮细胞（EC）特异性 ASM 转基因小鼠（Smpd1trg/ECcre）及其以西方饮食（WD）喂养的对照同窝小鼠（Smpd1trg/WT 和 WT/WT）进行部分左颈动脉结扎。我们发现，与对照同窝小鼠相比，Smpd1trg/ECcre 小鼠的新内膜形成显着增加。接下来，我们在 WD 处理的 Smpd1trg/ECcre 小鼠的颈动脉 EC 中观察到 NLRP3 相对于接头蛋白 ASC（包含 CARD 的接头分子凋亡相关斑点样蛋白）或 caspase-1 的共定位增强，但在其对照同窝小鼠中则没有。此外，我们使用膜筏 (MR) 标记物 flotillin-1，发现 Smpd1trg/ECcre 小鼠的内膜中 ASM 和神经酰胺的聚集比其对照同窝小鼠更多。此外，我们通过原位二氢乙锭染色证明，WD 处理的 Smpd1trg/ECcre 小鼠的颈动脉内膜超氧化物水平比其对照同窝小鼠高得多。使用来自 Smpd1trg/ECcre 和 WT/WT 小鼠的 EC，我们发现 ASM 过表达显着增强了 7-酮胆固醇 (7-Ket) 诱导的 NLRP3 炎症小体形成的增加，同时伴有 caspase-1 活性增强和白细胞介素 1β 水平升高。 ASM 抑制剂阿米替林显着减弱了这些 7-Ket 诱导的增加。此外，我们确定增加的 MR 与 NADPH 氧化酶亚基聚集产生超氧化物有助于通过硫氧还蛋白相互作用蛋白介导的控制机制促进 7-Ket 诱导的 NLRP3 炎症小体激活。我们得出的结论是，来自 ASM 的神经酰胺在高胆固醇血症期间通过 MR 氧化还原信号平台产生超氧化物，从而导致 TXNIP 解离，在 NLRP3 炎症小体激活中发挥关键作用。
The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome is activated during atherogenesis, but how this occurs is unclear. Here, we explored the mechanisms activating and regulating NLRP3 inflammasomes via the acid sphingomyelinase (ASM)-ceramide signaling pathway. As a neointima formation model, partial left carotid ligations were performed on endothelial cell (EC)-specific ASM transgene mice (Smpd1trg/ECcre) and their control littermates (Smpd1trg/WT and WT/WT) fed on the Western diet (WD). We found neointima formation remarkably increased in Smpd1trg/ECcre mice over their control littermates. Next, we observed enhanced colocalization of NLRP3 versus adaptor protein ASC (the adaptor molecule apoptosis-associated speck-like protein containing a CARD) or caspase-1 in the carotid ECs of WD-treated Smpd1trg/ECcre mice but not in their control littermates. In addition, we used membrane raft (MR) marker flotillin-1 and found more aggregation of ASM and ceramide in the intima of Smpd1trg/ECcre mice than their control littermates. Moreover, we demonstrated by in situ dihydroethidium staining, carotid intimal superoxide levels were much higher in WD-treated Smpd1trg/ECcre mice than in their control littermates. Using ECs from Smpd1trg/ECcre and WT/WT mice, we showed ASM overexpression markedly enhanced 7-ketocholesterol (7-Ket)-induced increases in NLRP3 inflammasome formation, accompanied by enhanced caspase-1 activity and elevated interleukin-1β levels. These 7-Ket-induced increases were significantly attenuated by ASM inhibitor amitriptyline. Furthermore, we determined that increased MR clustering with NADPH oxidase subunits to produce superoxide contributes to 7-Ket-induced NLRP3 inflammasome activation via a thioredoxin-interacting protein-mediated controlling mechanism. We conclude that ceramide from ASM plays a critical role in NLRP3 inflammasome activation during hypercholesterolemia via MR redox signaling platforms to produce superoxide, which leads to TXNIP dissociation.
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DOI：
10.1016/j.bbamcr.2014.11.012
发表时间：
2015-02
影响因子：
5.1
作者：
Chen, Yang;Li, Xiang;Boini, Krishna M.;Pitzer, Ashley L.;Gulbins, Erich;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan
影响因子：
4.7
作者：
Li, Xiang;Han, Wei-Qing;Boini, Krishna M.;Xia, Min;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan
影响因子：
5.3
作者：
Yi F;Jin S;Zhang F;Xia M;Bao JX;Hu J;Poklis JL;Li PL
通讯作者：
Li PL
DOI：
10.1161/hypertensionaha.114.03884
发表时间：
2014-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Abraham NG;Sodhi K;Silvis AM;Vanella L;Favero G;Rezzani R;Lee C;Zeldin DC;Schwartzman ML
通讯作者：
Schwartzman ML
影响因子：
4.8
作者：
Adamiak, Mateusz;Abdel-Latif, Ahmed;Ratajczak, Mariusz Z.
通讯作者：
Ratajczak, Mariusz Z.