Journal
DIABETES
Volume 70, Issue 3, Pages 772-787Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db20-0357
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Funding
- National Health and Medical Research Council (NHMRC)
- Diabetes Australia Research Trust general grant
- NHMRC [1145788, 1101405, 1183070, 1141466]
- NHMRC Project Grants
- Baker Fellowship
- operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme [9000220]
- Victorian State Government Operational Infrastructure Support, Australia
- National Health and Medical Research Council of Australia [1183070, 1145788, 1141466, 1101405] Funding Source: NHMRC
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This study found that inhibiting the NLRP3 inflammasome with MCC950 could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis. The results suggest that targeting NLRP3-mediated inflammation could be a novel therapeutic strategy to improve diabetes-related vascular disease.
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.
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