Projects per year
Abstract
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-1β (IL-1β). 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-1β, tumor necrosis factor-α, 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-1β 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.
Original language | English |
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Pages (from-to) | 772-787 |
Number of pages | 16 |
Journal | Diabetes |
Volume | 70 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2021 |
Keywords
- NLRP3 inflammasome
- ATHEROSCLEROSIS
- Inflammation
- IL-1 β
- Oxidative stress
Projects
- 3 Finished
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Unconventional mechanisms for activating the NLRP3 inflammasome
Vince, J., Murphy, J., Lawlor, K. & Lindqvist, L. M.
1/01/18 → 31/12/20
Project: Research
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Interleukin-1b biology: mechanisms of regulation, activation and secretion
Vince, J., Masters, S. L. & Harris, J.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/16 → 31/12/18
Project: Research
Equipment
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Monash Micro Imaging
Stephen Firth (Manager), Alex Fulcher (Operator), Oleks Chernyavskiy (Operator), Margaret Rzeszutek (Other), David Potter (Manager), Volker Hilsenstein (Operator), Juan Nunez-Iglesias (Other), Stephen Cody (Manager), Irena Carmichael (Operator), Betty Kouskousis (Other), Sarah Creed (Manager) & Giulia Ballerin (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility