Background: Thrombosis is the chief culprit in the fatal event of atherosclerotic cardiovascular disease (ASCVDs). Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools.Methods: The thrombi images, platelet activation makers and NETs makers were detected in the serum of 193 STEMI patients and 43 controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis in vivo, ApoE-/- Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK- cPLA2 signals inhibitors were used.Results: Thrombi were observed in the offender lesions in almost all STEMI patients, and serum IRGM was positively correlated with platelet factor 4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production.Conlusions: Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis. Targeting IRGM may represents a new therapeutic strategy that prevents and treats thrombosis during ASCVDs.Funding Information: This work was supported by the National Natural Science Foundation Projects [grant numbers 81870353 and 82170262 to S.F.], the Natural Science Foundation of Heilongjiang Province [grant number LH2020H048 and TD2020H001], and the 2nd Affiliated Hospital of Harbin Medical University, Harbin [grant number CX2016-21].Declaration of Interests: The authors have declared that no competing interest exists.Ethics Approval Statement: All experiments using human subjects were performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board Harbin Medical University. Written informed consent was obtained from participants before inclusion in the study.
Purpose: Inflammation and lipid accumulation are key events in atherosclerosis progression. Arsenic trioxide (ATO) has been reported to prevent vascular restenosis by promoting smooth muscle apoptosis and rapid intimalisation. However, its specific role and mechanism underlying its role in atherosclerosis remain unknown. Herein, we evaluated whether ATO suppressed atherosclerotic plaque development and instability.Methods: ApoE-/- mice were fed a high-fat diet for 3 months and treated with ATO every alternate day for 30 days. Aorta, carotid artery and serum samples were collected to determine atherosclerotic lesion size, histological features, and related protein and lipid profiles. In vitro, RAW264.7 or THP-1 cells were stimulated using oxidized low-density lipoprotein (ox-LDL) or LPS to explore the anti-inflammatory and anti-pyroptosis effects of ATO.Results: ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. Additionally, it reduced the pro-inflammatory factors levels, including IL-6 and TNF-α, in the serum and aortic plaques, but increased the IL-10 level. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a PPAR-γ dependent manner, which may explain the reduction in blood lipid levels. Further, ATO reduced TLR4 expression in plaques and macrophages and inhibited LPS-induced p65 nuclear translocation and IκB-α degradation.ConclusionATO has the potential atheroprotective effects, especially in macrophages. The mechanisms include inhibition of CD36-mediated foam cell formation, inflammatory responses, and pyroptosis via the suppression of TLR4/NF-κB and NLRP3 activation. Our findings provide evidence for the potential atheroprotective value of ATO.
Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear. ApoE-/- mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS). ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a peroxisome proliferator-activated receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and caspase 1 activation. ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.
Background and Purpose Inflammation and lipid accumulation are key events in atherosclerosis progression. Arsenic trioxide (ATO) has been reported to prevent vascular restenosis by promoting smooth muscle apoptosis and rapid initialization. However, its specific role and mechanism underlying its role in atherosclerosis remain unknown. Herein, we evaluated whether ATO suppresses atherosclerotic plaque development and instability. Experimental Approach ApoE-/- mice were fed a high-fat diet for 3 months and treated with ATO every alternate day for 30 days. The carotid artery and serum samples were collected to determine atherosclerotic lesion size, histological features, and related protein and lipid profiles. In vitro, RAW264.7 or THP-1 cells were stimulated using oxidized low-density lipoprotein (ox-LDL) or LPS to explore the anti-inflammatory and anti-pyroptosis effects of ATO. Key Results ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. Additionally, it reduced the levels of various pro-inflammatory factors, including IL-6 and TNFα, in the serum and aortic plaques, but increased the IL-10 level. Mechanistically, ATO promotes the CD36-mediated internalization of ox-LDL, which may explain the reduction in blood lipid levels. Further, ATO reduced TLR4 expression in plaques and macrophages and inhibited LPS-induced p65 nuclear translocation and IκB-α degradation. Conclusion and Implications ATO has the potential atheroprotective effects, especially in macrophages. The mechanisms include inhibition of CD36-mediated foam cell formation, inflammatory responses, and pyroptosis via the suppression of TLR4/NF-κB and NLRP3 activation. Our findings provide evidence for the potential atheroprotective value of ATO.
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