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.

• Authors: Hilman Zulkifli Amin, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Tomohiro Hayashi, Takuo Emoto, Takuya Matsumoto, Naofumi Yoshida, Tokiko Tabata, Sayo Horibe, Shoji Kawauchi, Yoshiyuki Rikitake, Ken-Ichi Hirata
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 8065 (05 30 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31147569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTLA-4 Antigen
• Ctla4 protein, mouse
• Angiotensin II

Topics

• Angiotensin II (toxicity)
• Animals
• Aorta, Abdominal (drug effects, immunology, pathology)
• Aortic Aneurysm, Abdominal (chemically induced, diagnosis, immunology, pathology)
• Aortic Rupture (chemically induced, immunology, pathology)
• Atherosclerosis (complications, immunology)
• CTLA-4 Antigen (genetics, immunology, metabolism)
• Diet, Atherogenic (adverse effects)
• Disease Models, Animal
• Humans
• Male
• Mice
• Mice, Knockout, ApoE
• Severity of Illness Index
• T-Lymphocytes (immunology, metabolism)