Unknown

Dataset Information

0

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


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.

SUBMITTER: Gao J 

PROVIDER: S-EPMC9929270 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Gao Jianing J   Chen Yanghui Y   Wang Huiqing H   Li Xin X   Li Ke K   Xu Yangkai Y   Xie Xianwei X   Guo Yansong Y   Yang Nana N   Zhang Xinhua X   Ma Dong D   Lu Hong S HS   Shen Ying H YH   Liu Yong Y   Zhang Jifeng J   Chen Y Eugene YE   Daugherty Alan A   Wang Dao Wen DW   Zheng Lemin L  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20221225 5


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-induc  ...[more]

Similar Datasets

| S-EPMC10393233 | biostudies-literature
| S-EPMC7530061 | biostudies-literature
2023-06-08 | GSE222440 | GEO
2020-11-21 | GSE153449 | GEO
| S-EPMC8880357 | biostudies-literature
| S-EPMC11008260 | biostudies-literature
| S-EPMC9546906 | biostudies-literature
| PRJNA922105 | ENA
2024-11-19 | GSE235161 | GEO
| S-EPMC7606768 | biostudies-literature