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Gasdermin D (GSDMD) is a pore\u2010forming effector of pyroptosis. In this study, the role of VSMC\u2010specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single\u2010cell transcriptome analyses reveal <jats:italic>Gsdmd<\/jats:italic> upregulation in aortic VSMCs in angiotensin (Ang) II\u2010induced AAA. VSMC\u2010specific <jats:italic>Gsdmd<\/jats:italic> deletion ameliorates Ang II\u2010induced AAA in apolipoprotein E (ApoE)<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC\u2010specific GSDMD deficient mice. High putrescine levels trigger a pro\u2010inflammatory phenotype in VSMCs and increase susceptibility to Ang II\u2010induced AAA formation in mice. In a population\u2010based study, a high level of putrescine in plasma is associated with the risk of AAA (<jats:italic>p<\/jats:italic> &lt; 2.2 \u00d7 10<jats:sup>\u221216<\/jats:sup>), consistent with the animal data. Mechanistically, GSDMD enhances endoplasmic reticulum stress\u2010C\/EBP homologous protein (CHOP) signaling, which in turn promotes the expression of ornithine decarboxylase 1 (ODC1), the enzyme responsible for increased putrescine levels. Treatment with the ODC1 inhibitor, difluoromethylornithine, reduces AAA formation in Ang II\u2010infused ApoE<jats:sup>\u2212\/\u2212<\/jats:sup> mice. The findings suggest that putrescine is a potential biomarker and target for AAA treatment.<\/jats:p>","DOI":"10.1002\/advs.202204038","type":"journal-article","created":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T22:52:48Z","timestamp":1672008768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Gasdermin D Deficiency in Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis"],"prefix":"10.1002","volume":"10","author":[{"given":"Jianing","family":"Gao","sequence":"first","affiliation":[{"name":"The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine School of Basic Medical Sciences Key Laboratory of Molecular Cardiovascular Science of Ministry of Education NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Health Science Center Peking University  Beijing 100191 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanghui","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Jiefang Avenue NO.1095, Qiaokou District Wuhan 430000 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine School of Basic Medical Sciences Key Laboratory of Molecular Cardiovascular Science of Ministry of Education NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Health Science Center Peking University  Beijing 100191 P. R. 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