Biejiajian Pill Ameliorates Diabetes-Associated Atherosclerosis through Inhibition of the NLRP3 Inflammasome

Abstract

Objective. To research the efficacy of Biejiajian pill (BJJ) on diabetes-associated atherosclerosis and explore its subsequent mechanisms. Methods. Diabetes-associated atherosclerosis (AS) was established in apolipoprotein E knockout (ApoE−/−) mice using high-fat diet and streptozotocin. Atorvastatin (ATV, 10 mg/kg/day) or BJJ-L (BJJ low-dose, 0.9 g/kg/day), BJJ-M (BJJ medium-dose, 1.8 g/kg/day), and BJJ-H (BJJ high-dose, 3.6 g/kg/day) were administered to diabetic ApoE−/− mice for 12 continuous weeks. The normal control group consisted of 10 male C57BL/6J mice. Atherosclerosis plaques, vascular endothelial function, fasting blood glucose, lipid metabolism, inflammatory factors, NLRP3 inflammasome expression, and mitochondria and autophagy changes were evaluated. Results. The atherosclerotic lesions areas in the aortas were analyzed through Oil Red O and H&E staining, and they were reduced in the BJJ-H and BJJ-M groups. In the BJJ group, endothelin-1 (ET-1) levels were decreased, whereas endothelial nitric oxide synthase (eNOS) was increased. Fasting blood glucose levels in the BJJ and ATV groups were gradually decreased. Lipid metabolism parameters such as TG, TC, and LDL-C were reduced, while HDL-C was elevated in BJJ groups. The serum IL-1β and IL-18 were decreased under BJJ therapy. The aortic mRNA and protein expressions of NF-κB, TXNIP, NLRP3, ASC, caspase-1, and IL-1β were inhibited in BJJ-H and BJJ-M groups, especially in the BJJ-H group. Electron microscopy revealed an increase in autophagy in each treatment group. Conclusions. The findings reveal that BJJ could alleviate diabetic atherosclerosis in diabetic ApoE−/− mice by inhibiting NLRP3 inflammasome.

Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets

“…The sequentially organized process of assembling an inflammasome usually involves a sensor protein, an adaptor protein, and an effector protein [12]. The NLRP3 inflammasome is a three-domain cytosolic protein compound consisting of three domains: a C-terminal leucine-rich repeat (LRR) domain, a central nucleotide-binding and oligomerization (NACHT/NOD) domain and an N-terminal effector PYD that interfaces with apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) [6,21,28].…”

“…Inhibiting diabetes-related atherosclerosis by raising eNOS levels and decreasing NF-κB and TXNIP expression in response to the priming signal from NLRP3 inflammasome activation, Biejiajian (BJJ), a traditional Chinese medicine, has lately exhibited promising results [12]. The LOX-1/NLRP3 pathway recently emerged as an important mediator in inflammasome activation upon the use of astragaloside IV (AS-IV), the active component of Astragalus membranaceus (Fisch.)…”

“…There is increasing evidence that damage-associated molecular patterns (DAMPs), alongside hyperglycemia and hyperlipidemia, are associated with the accelerated onset of atherosclerosis via NLRP3 inflammasomes [12,13]. Furthermore, it has been established that NLRP3 inflammasome associated with the activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) amplifies vascular endothelial cell (VECs) damage, monocyte adhesion and infiltration, vascular smooth muscle cell (VSMC) proliferation, and promotes secondary plaque vulnerability [14][15][16].…”