Specific NLRP3 inhibition protects against diabetes-associated atherosclerosis

Sharma, A; Choi, JSY; Stefanovic, N; Sharea, AA; Simpson, DS; Mukhamedova, N; Jandeleit-Dahm, K; Murphy, AJ; Sviridov, D; Vince, JE; Ritchie, RM; de Haan, JB

Author(s): Sharma, A; Choi, JSY; Stefanovic, N; Sharea, AA; Simpson, DS; Mukhamedova, N; Jandeleit-Dahm, K; Murphy, AJ; Sviridov, D; Vince, JE; Ritchie, RM; de Haan, JB;
Details: Publication Year 2021-03-01,Volume 70,Issue #3,Page 772-787
Journal Title: Diabetes
Abstract: Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the 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 (STZ)-induced diabetic Apolipoprotein knockout (ApoE(-/-)) mouse. Diabetes led to a ∼4-fold 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, TNFα, ICAM-1, MCP-1, P<0.05) and reduced oxidative stress, whilst 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 (BMDMs), human monocytic THP-1 cells, PMA-differentiated human macrophages and diabetic human aortic smooth muscle cells (AoSMCs)), MCC950 significantly reduced IL-1β and/or caspase-1 secretion and attenuated leukocyte-SMC interactions under high glucose or LPS 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.
Publisher: ADA
Research Division(s): Inflammation
PubMed ID: 33323396
Publisher's Version: https://doi.org/10.2337/db20-0357
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-02-01 12:08:35

Last Modified: 2021-03-02 03:13:37