A_Sharma_Online_Appendix_for_Diabetes_RESUBMISSION.pdf (815.56 kB)
Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis
figureposted on 2020-12-15, 19:26 authored by Ada AdminAda Admin, Arpeeta Sharma, Judy S.Y. Choi, Nada Stefanovic, Annas-Al Sharea, Daniel S. Simpson, Nigora Mukhamedova, Karin Jandeleit-Dahm, Andrew J. Murphy, Dmitri Sviridov, James E. Vince, Rebecca M. Ritchie, Judy B. de Haan
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.