American Diabetes Association
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Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis

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posted 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.


AS is supported by an early career fellowship from the National Health and Medical Research Council (NHMRC) and a Diabetes Australia Research Project (DARP) General Grant. JEV is supported by NHMRC Project Grants (1145788 and 1101405), an Ideas Grant (1183070) and a Fellowship (1141466). RR is supported by Project Grants and a Senior Research Fellowship from the NHMRC. JBDH is supported by a Baker Fellowship. This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support, Australia.


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