Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis

被引:113
作者
Sharma, Arpeeta [1 ,2 ]
Choi, Judy S. Y. [1 ]
Stefanovic, Nada [1 ]
Al-Sharea, Annas [1 ]
Simpson, Daniel S. [3 ,4 ]
Mukhamedova, Nigora [1 ]
Jandeleit-Dahm, Karin [2 ,5 ]
Murphy, Andrew J. [1 ]
Sviridov, Dmitri [1 ]
Vince, James E. [3 ,4 ]
Ritchie, Rebecca H. [1 ,6 ]
de Haan, Judy B. [1 ,7 ,8 ,9 ]
机构
[1] Baker Heart & Diabet Inst, Melbourne, Vic, Australia
[2] Monash Univ, Cent Clin Sch, Dept Diabet, Melbourne, Vic, Australia
[3] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia
[4] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia
[5] Heinrich Heine Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Dusseldorf, Germany
[6] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia
[7] Monash Univ, Cent Clin Sch, Dept Immunol & Pathol, Melbourne, Vic, Australia
[8] La Trobe Univ, Dept Physiol Anat & Microbiol, Melbourne, Vic, Australia
[9] Swinburne Univ, Fac Sci Engn & Technol, Melbourne, Vic, Australia
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
D O I
10.2337/db20-0357
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1 beta (IL-1 beta). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1 beta, tumor necrosis factor-alpha, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow-derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate-differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1 beta and/or caspase-1 secretion and attenuated leukocyte-smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease.
引用
收藏
页码:772 / 787
页数:16
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