High glucose levels accelerate atherosclerosis via NLRP3-IL/ MAPK/NF-κB-related inflammation pathways.

BACKGROUND: As a chronic inflammatory disease, diabetes mellitus (DM) contributes to the development of atherosclerosis (AS). However, how the NLRP3 inflammasome participates in diabetes-related AS remains unclear. Therefore, this study aimed to elucidate the mechanism through which NLRP3 uses high glucose (HG) levels to promote AS.

METHODS: Serum and coronary artery tissues were collected from coronary artery disease (CAD) patients with and without DM, respectively. The expression of NLRP3 was detected, and the effects of this inflammasome on diabetes-associated AS were evaluated using streptozotocin (STZ)-induced diabetic apoE-/- mice injected with Adenovirus-mediated NLRP3 interference (Ad-NLRP3i). To elucidate the potential mechanism involved, ox-LDL-irritated human aortic smooth muscle cells were divided into the control, high-glucose, Si-NC, and Si-NLRP3 groups to observe the changes induced by downregulating NLRP3 expression. For up-regulating NLRP3, control and plasmid contained NLRP3 were used. TNF-α, IL-1β, IL-6, IL-18, phosphorylated and total p38, JNK, p65, and IκBα expression levels were detected following the downregulation or upregulation of NLRP3 expression.

RESULTS: Patients with comorbid CAD and DM showed higher serum levels and expression of NLRP3 in the coronary artery than those with only CAD. Moreover, mice in the Ad-NLRP3i group showed markedly smaller and more stable atherosclerotic lesions compared to those in other DM groups. These mice had decreased inflammatory cytokine production and improved glucose tolerance, which demonstrated the substantial effects of NLRP3 in the progression of diabetes-associated AS. Furthermore, using the siRNA or plasmid to downregulate or upregulate NLRP3 expression in vitro altered cytokines and the MAPK/NF-κB pathway.

CONCLUSIONS: NLRP3 expression was significantly increased under hyperglycemia. Additionally, it accelerated AS by promoting inflammation via the IL/MAPK/NF-κB pathway.