2021 Fiscal Year Final Research Report
Kv1.5 channel mediates monosodium urate-induced activation of NLRP3 inflammasome in macrophages and arrhythmogenic effects of urate on cardiomyocytes
| Project/Area Number |
18K08074
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Tottori University |
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Principal Investigator |
LI Peili 鳥取大学, 医学部, 特命助教 (40464292)
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| Co-Investigator(Kenkyū-buntansha) |
久留 一郎 鳥取大学, 医学(系)研究科(研究院), 教授 (60211504)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Keywords | Kv1.5 / NLRP3 inflammasome / Monosodium urate / atrial fibrillation / Heat shock protein |
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| Outline of Final Research Achievements |
Gout is commonly found in patients with atrial fibrillation (AF). We found that a K+ channel Kv1.5 regulates monosodium urate crystal (MSU)-induced NLRP3 inflammasome activation and electrical remodeling in mouse macrophages J774.1 and atrial myocytes HL-1. Kv1.5 inhibitor or knockdown of Kv1.5 by siRNAs suppressed the NLRP3 inflammasome activation. MSU increased expression of Hsp70, and Kv1.5. a siRNA against Hsp70 were suppressed but heat shock activated the NLRP3 inflammasome in MSU-stimulated J774.1 cells. Incubations of HL-1 cells with the conditioned medium (CM) from MSU-stimulated macrophages activated the NLRP3 inflammasome and enhanced Kv1.5 protein expression with increased Kv1.5-mediated currents that shortened action potential duration in HL-1 cells. These responses were abolished by DPO-1 and a siRNA against Kv1.5. These results indicate that Kv1.5 regulates MSU-induced NLRP3 inflammasome activation in macrophages and electrical remodeling in HL-1 cells.
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| Free Research Field |
循環器内科学
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| Academic Significance and Societal Importance of the Research Achievements |
高尿酸血症や痛風による炎症又心房細動に対する新規治療薬および治療法開発の重要性は高齢化に伴い益々高まっており、NLRP3インフラマソーム活性化による自然免疫に関する研究は今後最も重要視される領域の一つである。本研究成果は、Kv1.5チャネルが尿酸結晶によるマクロファージでのNLRP3インフラマソーム活性化し、その分泌成分が心房筋でのNLRP3インフラマソームを活性化および電気的リモデリングを引き起こし、心房細動発生に寄与することを明らかにした。Kv1.5チャネルは高尿酸血症による痛風および心房細動の治療標的なり得ると考えている。
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