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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-1\u03b2 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-1\u03b2 and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.<\/jats:p>","DOI":"10.3390\/biom14060726","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T03:46:29Z","timestamp":1718855189000},"page":"726","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Gasdermin D Inhibitor Necrosulfonamide Alleviates Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Jia","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, First Hospital Shanxi Medical University, Taiyuan 030001, Shanxi, China"},{"name":"Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, First Hospital Shanxi Medical University, Taiyuan 030001, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhidong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, First Hospital Shanxi Medical University, Taiyuan 030001, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyun","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, First Hospital Shanxi Medical University, Taiyuan 030001, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5375-4557","authenticated-orcid":false,"given":"Wenjia","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Samura","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S","family":"Tsao","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"VA Palo Alto Health Care System, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-7464","authenticated-orcid":false,"given":"Baohui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"VA Palo Alto Health Care System, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1097\/SLA.0000000000005716","article-title":"The global and regional prevalence of abdominal aortic aneurysms: A systematic review and modeling analysis","volume":"277","author":"Song","year":"2023","journal-title":"Ann. 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