Abdominal aortic aneurysm (AAA) is a common vascular disease associated with significant phenotypic alterations in vascular smooth muscle cells (VSMCs). Gasdermin D (GSDMD) is a pore-forming effector of pyroptosis. In this study, the role of VSMC-specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single-cell transcriptome analyses reveal Gsdmd upregulation in aortic VSMCs in angiotensin (Ang) II-induced AAA. VSMC-specific Gsdmd deletion ameliorates Ang II-induced AAA in apolipoprotein E (ApoE)−/− mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC-specific GSDMD deficient mice. High putrescine levels trigger a pro-inflammatory phenotype in VSMCs and increase susceptibility to Ang II-induced AAA formation in mice. In a population-based study, a high level of putrescine in plasma is associated with the risk of AAA (p < 2.2 × 10−16), consistent with the animal data. Mechanistically, GSDMD enhances endoplasmic reticulum stress-C/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-infused ApoE−/− mice. The findings suggest that putrescine is a potential biomarker and target for AAA treatment.
|State||Published - Feb 14 2023|
Bibliographical noteFunding Information:
The authors thank Prof. Guotao Lu for GSDMD flox (GSDMD) mice. This work was supported by the National Natural Science Foundation of China (91639108, 81770272, 81970425, 91839302), by the National High Technology Research and Development Program of China (2020YFA0803700), by the Hangzhou Qianjiang Distinguished Expert Project (L.Z.), and by the Fundamental Research Funds for the Central Universities (HUST: YCJJ202201016). All animal experiments were performed according to the regulations approved by the Peking University Institutional Animal Care and Use Committee (LA2017004). fl/fl
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
- abdominal aortic aneurysm
- gasdermin D
- smooth muscle cells
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Chemical Engineering (all)
- Materials Science (all)
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Engineering (all)
- Physics and Astronomy (all)