Activating α7nAChR ameliorates abdominal aortic aneurysm through inhibiting pyroptosis mediated by NLRP3 inflammasome

Abstract

Abdominal aortic aneurysm (AAA) is defined as a dilated aorta in diameter at least 1.5 times of a normal aorta. Our previous studies found that activating α7 nicotinic acetylcholine receptor (α7nAChR) had a protective effect on vascular injury. This work was to investigate whether activating α7nAChR could influence AAA formation and explore its mechanisms. AAA models were established by angiotensin II (Ang II) infusion in ApoE−/− mice or in wild type and α7nAChR−/− mice. In vitro mouse aortic smooth muscle (MOVAS) cells were treated with tumor necrosis factor-α (TNF-α). PNU-282987 was chosen to activate α7nAChR. We found that cell pyroptosis effector GSDMD and NLRP3 inflammasome were activated in abdominal aorta, and inflammatory cytokines in serum were elevated in AAA models of ApoE−/− mice. Activating α7nAChR reduced maximal aortic diameters, preserved elastin integrity and decreased inflammatory responses in ApoE−/− mice with Ang II infusion. While α7nAChR−/− mice led to aggravated aortic injury and increased inflammatory cytokines with Ang II infusion when compared with wild type. Moreover, activating α7nAChR inhibited NLRP3/caspase-1/GSDMD pathway in AAA model of ApoE−/− mice, while α7nAChR deficiency promoted this pathway. In vitro, N-acetylcysteine (NAC) inhibited NLRP3 inflammasome activation and NLRP3 knockdown reduced GSDMD expression, in MOVAS cells treated with TNF-α. Furthermore, activating α7nAChR inhibited oxidative stress, reduced NLRP3/GSDMD expression, and decreased cell pyroptosis in MOVAS cells with TNF-α. In conclusion, our study found that activating α7nAChR retarded AAA through inhibiting pyroptosis mediated by NLRP3 inflammasome. These suggested that α7nAChR would be a potential pharmacological target for AAA.

α7 Nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect

“…Interestingly, using α-BGT at the dose (1 μg/kg/d) did not reverse the inhibitory effects of DMXBA on the activation of microglia [ 184 ]. Deng et al showed that the activation of α7 nAChR could significantly inhibit the expression of NLRP3 inflammasome; this result was consistent with those of a study by Fu [ 201 , 202 ]. Furthermore, activating the α7 nAChR could also attenuate OS [ 216 ].…”

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

“…SNPs involving all the above-mentioned RAAS molecules, ( ACE/ACE2/AGT/AGTR1 ), while protective in malaria, have been implicated in severe adult COVID-19 outcomes (Table 2 ) [ 104 , 106 , 115 ]. Their net haplotype effect could significantly impact Ang II and EPO levels, eNOS activity, NO generation and bioavailability, perturbing NLRP3 inflammasome regulation, endothelial function, peripheral vascular resistance, and blood pressure (Table 2 ) [ 52 , 57 , 58 , 108 – 110 , 116 ].…”

Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways

“…6 B). PXDN has been previously suggested to catalyze hypochlorous acid (HOCL) generation in HO, which also markedly increases the ROS production and the inflammatory response [ 15 , 16 ]. PXDN is the new signal node mediating the phenotype change of VSMCs, which also has an important effect on AAA formation [ 17 ].…”

“…This work acquired mouse aortic smooth muscle cells (MOVAS) in American Type Culture Collection (ATCC). For establishing the aneurysmal microenvironment within MOVAS, this work adopted TNF-α for stimulating MOVAS [ 15 , 16 ]. The MOVAS cell line was grown in DMEM media that contained 1% penicillin/streptomycin and 10% fetal bovine serum (FBS), followed by incubation under 5% CO2 and 37 °C conditions.…”