Abstract 9990: Activation of Natural Killer T Cells Ameliorates the Development of Angiotensin II-mediated Abdominal Aortic Aneurysm Formation in Obese ob/ob Mice
Objective: Abdominal aortic aneurysm (AAA) is strongly associated with common atherosclerotic risk factors such as male gender, age, smoking, hypertension, and dyslipidemia. Its underlying cause has been considered to be atherosclerosis in which chronic inflammation including various pro-inflammatory cytokines within the vasculature is involved. We have demonstrated that natural killer T (NKT) 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 and its plaque rupture as well as metabolic derangements in obese mice. However, it remains unclear that NKT cells are also involved in the development of AAA.
Methods and Results: Male obese ob/ob mice were administered angiotensin II (AngII, 1000ng/kg/min; n=18) or phosphate buffered saline (PBS; n=10) with osmotic minipumps for 4 weeks. The AngII-administered mice were further divided into 2 groups; α-galactosylceramide (αGC, 0.1 μ g/g body weight intraperitoneal injection; AngII-αGC; n=12), which specifically activates NKT cells, and PBS (AngII-PBS; n=6). The maximal abdominal aortic diameter was significantly greater in AngII-PBS than in PBS (1726±288 vs. 833±69 µm, p<0.01). AngII administration significantly enhanced mRNA expression of the activation markers of macrophages, F4/80 and major histocompatibility complex (MHC)-class II, by 2.5-folds and 4.6-folds (p<0.05 each), and matrix metalloproteinase-2 (MMP-2) by 5.0-folds (p<0.01) in aortic tissues from AngII-PBS mice. αGC injection significantly ameliorated the AngII-mediated increase of aortic diameter in AngII-αGC (1241±257 µm, p<0.01 vs. AngII-PBS) without affecting the blood pressure (145±6 vs. 154±5 mmHg, p=N.S.).
Conclusions: AngII induces AAA in obese ob/ob mice via activating macrophage infiltration and up-regulation of MMP-2 within the vascular tissues. The activation of NKT cells can ameliorate the development of AAA. Regulation of NKT cell activation may be a novel therapeutic strategy against AAA.
- © 2012 by American Heart Association, Inc.