Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia
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,...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227522001316 |
| _version_ | 1811289910049505280 |
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| author | Xinxu Yuan Owais M. Bhat Yao Zou Xiang Li Yang Zhang Pin-Lan Li |
| author_facet | Xinxu Yuan Owais M. Bhat Yao Zou Xiang Li Yang Zhang Pin-Lan Li |
| author_sort | Xinxu Yuan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T04:03:31Z |
| format | Article |
| id | doaj.art-96c9c5b6f88f44d9b1520687c7ec07ea |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-13T04:03:31Z |
| publishDate | 2022-12-01 |
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| series | Journal of Lipid Research |
| spelling | doaj.art-96c9c5b6f88f44d9b1520687c7ec07ea2022-12-22T03:03:24ZengElsevierJournal of Lipid Research0022-22752022-12-016312100298Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During HypercholesterolemiaXinxu Yuan0Owais M. Bhat1Yao Zou2Xiang Li3Yang Zhang4Pin-Lan Li5Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USADepartment of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USADepartment of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USADepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USADepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USADepartment of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; For correspondence: Pin-Lan LiThe 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.http://www.sciencedirect.com/science/article/pii/S0022227522001316carotid arteryendothelial cellslysosomal ceramideredox signalingamitriptylineNADPH |
| spellingShingle | Xinxu Yuan Owais M. Bhat Yao Zou Xiang Li Yang Zhang Pin-Lan Li Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia Journal of Lipid Research carotid artery endothelial cells lysosomal ceramide redox signaling amitriptyline NADPH |
| title | Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia |
| title_full | Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia |
| title_fullStr | Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia |
| title_full_unstemmed | Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia |
| title_short | Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia |
| title_sort | endothelial acid sphingomyelinase promotes nlrp3 inflammasome and neointima formation during hypercholesterolemia |
| topic | carotid artery endothelial cells lysosomal ceramide redox signaling amitriptyline NADPH |
| url | http://www.sciencedirect.com/science/article/pii/S0022227522001316 |
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