Abstract
The infiltration and activation of macrophages as well as lymphocytes within the aorta contribute to the pathogenesis of abdominal aortic aneurysm (AAA). Invariant natural killer T (iNKT) cells are unique subset of T lymphocytes and have a crucial role in atherogenesis. However, it remains unclear whether iNKT cells also impact on the development of AAA. Ob/ob mice were administered angiotensin II (AngII, 1,000 ng/kg/min) or phosphate-buffered saline (PBS) by osmotic minipumps for 4 weeks and further divided into 2 groups; α-galactosylceramide (αGC; PBS-αGC; n = 5 and AngII-αGC; n = 12), which specifically activates iNKT cells, and PBS (PBS-PBS; n = 10, and AngII-PBS; n = 6). Maximal abdominal aortic diameter was comparable between PBS-PBS and PBS-αGC, and was significantly greater in AngII-PBS than in PBS-PBS. This increase was significantly attenuated in AngII-αGC without affecting blood pressure. αGC significantly enhanced iNKT cell infiltration compared to PBS-PBS. The ratio of F4/80-positive macrophages or CD3-positive T lymphocytes area to the lesion area was significantly higher in AngII-PBS than in PBS-PBS, and was significantly decreased in AngII-αGC. Gene expression of M2-macrophage specific markers, arginase-1 and resistin-like molecule alpha, was significantly greater in aortic tissues from AngII-αGC compared to AngII-PBS 1 week after AngII administration, and this increase was diminished at 4 weeks. Activation of iNKT cells by αGC can attenuate AngII-mediated AAA in ob/ob mice via inducing anti-inflammatory M2 polarized state. Activation of iNKT cells by the bioactive lipid αGC may be a novel therapeutic target against the development of AAA.
Highlights
Abdominal aortic aneurysm (AAA) is a common disease that affects 5% of men over the age of 65 years [1]
The present study demonstrated that angiotensin II (AngII) infusion in obese ob/ob mice developed abdominal aortic aneurysm (AAA) formation with the accumulating of macrophages and T lymphocytes within the vascular tissues, and local degeneration of the medial extracellular matrix
The activation of Invariant natural killer T (iNKT) cells by αGC attenuated the development of AngII-mediated AAA formation via inhibiting the infiltration of macrophages and T lymphocytes within the vascular tissues and inducing M2 macrophage infiltration at early phase
Summary
Abdominal aortic aneurysm (AAA) is a common disease that affects 5% of men over the age of 65 years [1]. The risk of the rupture of AAA increases with increasing aortic diameter and it often results in high mortality [2, 3]. Despite the high prevalence of this disease, there is no effective pharmacological therapy that reduces the diameter of AAA. Inflammatory cell infiltration within the aortic wall plays an important role during the process of AAA formation by releasing cytokines and proteases [5,6,7,8]. Macrophage infiltration and proinflammatory cytokine expression in periaortic adipose tissue surrounding abdominal aortas enhances AAA formation in mice [9]
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