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
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.
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页数:15
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