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

被引：33

作者：

Gao, Jianing ^{[1
,2
]}

Chen, Yanghui ^{[3
,4
]}

Wang, Huiqing ^{[1
,2
]}

Li, Xin ^{[1
,2
]}

Li, Ke ^{[5
]}

Xu, Yangkai ^{[1
,2
]}

Xie, Xianwei ^{[6
]}

Guo, Yansong ^{[7
]}

Yang, Nana ^{[8
]}

Zhang, Xinhua ^{[9
]}

Ma, Dong ^{[10
]}

Lu, Hong S. ^{[11
]}

Shen, Ying H. ^{[12
]}

Liu, Yong ^{[13
]}

Zhang, Jifeng ^{[14
]}

Chen, Y. Eugene ^{[14
]}

Daugherty, Alan ^{[11
]}

Wang, Dao Wen ^{[3
,4
]}

Zheng, Lemin ^{[1
,2
,5
,15
]}

机构：

[1] Peking Univ, Inst Cardiovasc Sci, Beijing 100191, Peoples R China

[2] Peking Univ, Inst Syst Biomed,Hlth Sci Ctr, Sch Basic Med Sci,Beijing Key Lab Cardiovasc Rece, Key Lab Mol Cardiovasc Sci Minist Educ,NHC Key La, Beijing 100191, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol,Dept Internal Med, Jiefang Ave 1095, Wuhan 430000, Peoples R China

[4] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Jiefang Ave 1095, Wuhan 430000, Peoples R China

[5] Capital Med Univ, Beijing Tiantan Hosp, China Natl Clin Res Ctr Neurol Dis, Adv Innovat Ctr Human Brain Protect,Beijing Inst, Beijing 100050, Peoples R China

[6] Fujian Med Univ, Fujian Prov Hosp, Shengli Clin Med Coll, Fuzhou 350001, Peoples R China

[7] Fujian Med Univ, Fujian Prov Hosp,Fujian Heart Failure Ctr Allianc, Fujian Prov Ctr Geriatr,Dept Cardiol,Fujian Prov, Fujian Clin Med Res Ctr Cardiovasc Dis,Shengli Cl, Fuzhou 350001, Peoples R China

[8] Weifang Med Univ, Weifang Key Lab Anim Model Res Cardiovasc & Cereb, Weifang 261053, Peoples R China

[9] Hebei Med Univ, Dept Biochem & Mol Biol, Key Lab Neural & Vasc Biol, Minist Educ, Zhongshan East Rd 361, Shijiazhuang 050017, Hebei, Peoples R China

[10] Hebei Med Univ, Dept Biochem & Mol Biol, Key Lab Neural & Vasc Biol, China Adm Educ, Shijiazhuang 050017, Hebei, Peoples R China

[11] Univ Kentucky, Saha Cardiovasc Res Ctr, Dept Physiol, Lexington, KY 40536 USA

[12] Baylor Coll Med, Texas Heart Inst, Michael E DeBakey Dept Surg, Dept Cardiovasc Surg,Div Cardiothorac Surg, Houston, TX 77030 USA

[13] Wuhan Univ, Coll Life Sci, Inst Adv Studies, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Peoples R China

[14] Univ Michigan, Dept Internal Med, Med Ctr, Ann Arbor, MI 48109 USA

[15] Hangzhou Inst Adv Technol, Hangzhou Qianjiang Distinguished Expert, Hangzhou 310026, Peoples R China

来源：

ADVANCED SCIENCE | 2023年 / 10卷 / 05期

基金：

中国国家自然科学基金; 国家高技术研究发展计划(863计划);

关键词：

abdominal aortic aneurysm; gasdermin D; putrescine; smooth muscle cells; ENDOPLASMIC-RETICULUM STRESS; ORNITHINE-DECARBOXYLASE; TRANSMEMBRANE PROTEIN; POLYAMINE METABOLISM; DIFLUOROMETHYLORNITHINE; CANCER; PROLIFERATION; DEGENERATION; TRANSLATION; DISSECTION;

D O I：

10.1002/advs.202204038

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 x 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.

引用

页数：15

共 74 条

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