Gasdermin D Deficiency in Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis

Authors

Jianing Gao, Peking University
Yanghui Chen, Huazhong University of Science and Technology
Huiqing Wang, Peking University
Xin Li, Peking University
Ke Li, The Capital Medical University
Yangkai Xu, Peking University
Xianwei Xie, Fujian Provincial Hospital
Yansong Guo, Fujian Heart Failure Center Alliance
Nana Yang, Weifang Medical University
Xinhua Zhang, Hebei Medical University
Dong Ma, Hebei Medical University
Hong S. Lu, University of KentuckyFollow
Ying H. Shen, Texas Heart Institute
Yong Liu, Wuhan University
Jifeng Zhang, University of Michigan - Ann Arbor
Y. Eugene Chen, University of Michigan - Ann Arbor
Alan Daugherty, University of KentuckyFollow
Dao Wen Wang, Huazhong University of Science and TechnologyFollow
Lemin Zheng, Peking UniversityFollow

Abstract

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.

Document Type

Article

Publication Date

2-2023

Notes/Citation Information

© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH

Digital Object Identifier (DOI)

https://doi.org/10.1002/advs.202204038

Funding Information

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).

Repository Citation

Gao, Jianing; Chen, Yanghui; Wang, Huiqing; Li, Xin; Li, Ke; Xu, Yangkai; Xie, Xianwei; Guo, Yansong; Yang, Nana; Zhang, Xinhua; Ma, Dong; Lu, Hong S.; Shen, Ying H.; Liu, Yong; Zhang, Jifeng; Chen, Y. Eugene; Daugherty, Alan; Wang, Dao Wen; and Zheng, Lemin, "Gasdermin D Deficiency in Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis" (2023). Saha Cardiovascular Research Center Faculty Publications. 85.
https://uknowledge.uky.edu/cvrc_facpub/85