Abstract
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.
Highlights
Accumulating evidence suggests that chronic inflammation of the arterial wall is critically involved in the pathogenesis of abdominal aortic aneurysm (AAA)
Angiotensin II infusion for 4 weeks led to a marked elevation in systolic blood pressure (SBP) in both 16-week-old Apoe−/− and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4)-Tg/Apoe−/− mice, whereas there was no significant difference in SBP between the 2 groups (Supplemental Table 1)
We found a significant decrease in the incidence (66%, P = 0.0104) and mortality (26%, P = 0.031) of AAA in angiotensin II-infused CTLA-4-Tg/Apoe−/− mice (Fig. 1B–E)
Summary
Www.nature.com/scientificreports costimulatory signals provided by costimulatory molecules on antigen-presenting cells, which play indispensable roles in enhancing or inhibiting activation of Teffs, depending on the type of costimulation. Recent experimental studies using genetically modified mice or blocking antibodies have revealed that the costimulatory and coinhibitory pathways are critically involved in the pathogenesis of atherosclerosis[7]. The coinhibitory molecule cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), expressed in activated T cells and CD4+Foxp3+ Tregs, binds to CD80 and CD86 on antigen-presenting cells and negatively regulates T cell function. Our recent work using atherosclerosis-prone CTLA-4 transgenic (CTLA-4-Tg) mice demonstrated a protective role of this inhibitory molecule in the development of experimental atherosclerosis[12] It is unknown whether CTLA-4 plays a protective role in the development of atherosclerosis-related cardiovascular diseases such as AAA. Using hypercholesterolemic CTLA-4-Tg mice constitutively expressing CTLA-4 on the cell surface and intracellularly in T cells[12,13], we explored the role of CTLA-4 in the development of experimental AAA
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