Abstract 10236: Natural Killer T Cells are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Deficient Mice
Objective: The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. 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 atherogenesis. However, it remains unclear whether NKT cells are involved also in plaque instability.
Methods: Male apolipoprotein E (apoE) deficient mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. The SD- and the HFD-fed mice were divided into 2 groups according to the injection of α-galactosylceramide (αGC, 2μg/body, intraperitoneally twice a week; SD-αGC and HFD-αGC; n=7 and n=21, respectively) that specifically activates NKT cells or phosphate-buffered saline (PBS; SD-PBS and HFD-PBS; n=6 and n=21, respectively). Plaque instability was assessed at the brachiocephalic artery by the histological analysis. The expression levels of inflammatory genes were quantified in aortic tissues including aortic arch and brachiocephalic artery.
Results: αGC injection did not affect the serum lipid levels and plasma fasting glucose in both diet groups. αGC increased NKT cell infiltration by 1.9-folds in aortic tissues from the HFD group. Activation of NKT cells by αGC significantly increased the number of buried fibrous caps, signs of previous plaque ruptures, (1.0±0.2 vs. 0.4±0.1/section, p<0.01), disrupted elastic laminae (0.8±0.2 vs. 0.3±0.1/section, p<0.01), and reduced fibrous cap thickness (5.2±0.6 vs. 7.9±0.7μm, p<0.01) in HFD-αGC compared to HFD-PBS mice without affecting atherosclerotic lesion area. Real-time PCR analyses demonstrated that αGC significantly enhanced the major histocompatibility complex (MHC)-class II, regulated on activation, normal T cell expressed and secreted (RANTES), interferon (IFN)-γ, and matrix metalloproteinase (MMP)-2 expression in aortic tissues from HFD-fed mice.
Conclusions: NKT cells are involved in the enhancement of plaque instability via activating macrophages and T lymphocytes and up-regulation of MMP-2 in vascular tissues.
- © 2010 by American Heart Association, Inc.