CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice

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.

Circulating Treg cells from patients with cerebral aneurysms displayed deficiency in ICOS expression and function

“…It is thought that IL‐10 production and CD28‐CD80/CD86 interaction are involved in Treg‐mediated protection against aneurysms 10,11 . In addition, CTLA‐4, an inhibitory molecule constitutively expressed by Treg cells, is shown to reduce aneurysm formation and mortality 12 …”

Adipose-Derived Mesenchymal Stem Cells Isolated from Patients with Abdominal Aortic Aneurysm Exhibit Senescence Phenomena

“…The incidence of AAA in the aging population is estimated to be 6 to 9% [2]. Although the underlying mechanisms are not fully understood, chronic inflammation of the arterial wall is known to play a critical role in regulating its pathogenesis [3–5]. Despite the advances in pharmacological strategies including macrolides, tetracyclines, statins, and surgical interventions, there remains no effective treatment to prevent AAA progression and rupture [6].…”

Cytotoxic T Lymphocyte-Associated Antigen-4 Protects Against Angiotensin II-Induced Kidney Injury in Mice

“…Amelioration of AngII-Induced KI CTLA-4 overexpression did not change mouse body weight or plasma lipid profile. 7 Although there was a marked increase in systolic blood pressure (SBP) in both Apoe −/− and CTLA-4-Tg/ Apoe −/− mice following AngII infusion for 4 weeks, there was no difference in SBP between the 2 groups. 7 We next evaluated the effect of AngII infusion on morphological changes in kidney structure in both Apoe −/− and CTLA-4-Tg/ Apoe −/− mice by evaluating HE-stained cryosections.…”

“…We implanted ALZET mini-osmotic pumps (Model 2004; DURECT, Cupertino, CA, USA) in 12-week-old mice under anesthesia and continuously infused AngII (1,000 ng/kg/min, Sigma, St Louis, MO, USA) for 28 days as described previously. 7 The mice were killed at 16 weeks of age under anesthesia to evaluate KI. The mice were housed in specific pathogen-free animal facilities.…”

“…We recently generated CTLA-4 transgenic (CTLA-4-Tg) mice on an atherosclerosis-prone background and demonstrated that overexpression of CTLA-4 protected against the development of immunoinflammatory diseases of the arteries such as atherosclerosis 6 and abdominal aortic aneurysm. 7 However, the effect of CTLA-4 overexpression on kidney disease remains unknown. In the present study, we used the CTLA-4-Tg mice that we have recently established, to investigate the role of CTLA-4 in the development of AngII-induced experimental kidney disease.…”