RESUMO
Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4+ T cells, CD8+ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1ß and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1ß and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.
Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Apolipoproteínas E , Sulfonamidas , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Camundongos , Masculino , Sulfonamidas/farmacologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Proteínas de Ligação a Fosfato/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Indóis/farmacologia , Camundongos Knockout para ApoE , GasderminasRESUMO
PURPOSE: Our aim is to verify the association of three Single nucleotide polymorphisms (SNPs) (-218A/G, -254C/G, -361A/T) in the promoter of TRPC6 in 168 sporadic cases with infantile hypertrophic pyloric stenosis (IHPS) and 164 controls in Chinese people. METHODS: All participants were genotyped using polymerase chain reaction and direct sequencing. And the χ(2) value was calculated. A value of P less than 0.05 was considered statistically significant. We also got the P value of Hardy-Weinberg equilibrium test, and the value of P greater than 0.05 was assumed to be at Hardy-Weinberg equilibrium in this population. RESULTS: The results tell us that there are no significant differences in the allele and genotype frequencies of all these three SNPs between the case and the control groups (P > 0.05). CONCLUSION: These three TRPC6 SNPs have no association with the IHPS in Chinese people. However, we cannot deny that TRPC6 would be a susceptible gene with IHPS in Chinese people. May be other SNPs in TRPC6 would have some association with the IHPS in Chinese people. But in this study our results may be due to the fact that these SNPs are not the functional SNPs for the development of IHPS in Chinese people.