Abstract 11427: Activation of Invariant Natural Killer T Cells Ameliorates the Development of Angiotensin II-Mediated Abdominal Aortic Aneurysm Formation in Obese ob/ob Mice
Objective: The infiltration and activation of macrophages and lymphocytes within the vascular wall contribute to the pathogenesis of abdominal aortic aneurysm (AAA). We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes which recognize glycolipid antigens and secrete a large amount of Th1/Th2 cytokines on activation, have a crucial role in the development of atherosclerosis in obese mice. However, it remains unclear whether iNKT cells are involved also in the development of AAA.
Methods and Results: Male obese ob/ob mice were administered angiotensin II (AngII, 1000 ng/kg/min; n=18) or phosphate buffered saline (PBS; n=10) via osmotic minipumps for 4 weeks. AngII-administered mice were further divided into 2 groups; α-galactosylceramide (αGC, 0.1 μg/g body weight intraperitoneal injection; AngII-αGC; n=12), which specifically activates iNKT cells, and PBS (AngII-PBS; n=6). The maximal abdominal aortic diameter was significantly greater in AngII-PBS than in PBS alone (1726±288 vs. 833±69 μm, P<0.01). The ratio of CD3-positive T lymphocytes or F4/80-positive macrophages area to the aortic lesion area was significantly higher in AngII-PBS than in PBS (7.0±0.5 vs. 2.1±0.5 % and 7.7±0.7 vs. 1.6±0.2 %, both P<0.001). Gene expression of the activation marker of macrophages, F4/80, and major histocompatibility complex (MHC)-class II, was significantly enhanced by 2.5-folds and 4.6-folds, respectively, (both P<0.05) in aortic tissues from AngII-PBS mice. In addition, matrix metalloproteinase-2 (MMP-2) gene expression was also increased by 5.0-folds (P <0.01) in AngII-PBS mice. AngII-mediated increase of abdominal aortic diameter was significantly ameliorated in AngII-αGC (1241±257 μm, P<0.01 vs. AngII-PBS) without affecting blood pressure (145±6 vs. 154±5 mmHg, P=NS).
Conclusions: AngII induced AAA in obese ob/ob mice in association with activating macrophages as well as T lymphocytes and up-regulating MMP-2 within the vascular tissues, which could be ameliorated by the activation of iNKT cells. Regulation of iNKT cell activation may be a novel therapeutic strategy against AAA.
- © 2013 by American Heart Association, Inc.