期刊
SCIENTIFIC REPORTS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-44523-6
关键词
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资金
- JSPS [15K09156, 18K08088]
- Pfizer Research Grant
- Astellas Research Grant
- Novartis Research Grant
- Uehara Memorial Foundation
- Kanae Medical Foundation
- Senshin Medical Research Foundation
- Hyogo Science and Technology Association
- Takeda Scientific Foundation
- Suzuken Memorial Foundation
- Grants-in-Aid for Scientific Research [15K09156, 18K08088] Funding Source: KAKEN
Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E-deficient (Apoe(-/-)) mice or control Apoe(-/-) mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4(+) T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c(+) dendritic cells in lymphoid tissues. CTLA-4-Tg/Apoe(-/-)mice had reduced accumulation of macrophages and CD4(+) T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.
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