Abstract 11951: Invariant Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout 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 invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes, play a crucial role in atherogenesis. However, it remains unclear whether iNKT cells are involved also in plaque instability.
Methods and Results: Male apolipoprotein-E (apoE) knockout mice were fed with a high-fat diet (HFD) from 8 to 16 weeks and divided into 2 groups according to the administration of α-galactosylceramide (αGC; HFD-αGC, n=21), which specifically activates iNKT cells, or phosphate-buffered saline alone (PBS; HFD-PBS, n=21). Male apoE/Jα18 double knockout mice, which lack iNKT cells, were also fed with HFD (HFD-KO, n=9). Plaque instability was assessed at the brachiocephalic artery by the histological analysis. αGC administration significantly enhanced iNKT cell infiltration by 1.9-folds in aortic tissues from HFD-fed mice (P≤0.01). The number of buried fibrous caps and disrupted elastic laminae were significantly greater in HFD-αGC compared than in HFD-PBS (1.0±0.2 vs. 0.4±0.1/slice and 0.8±0.2 vs. 0.3±0.1/slice, respectively, both P≤0.05) without affecting atherosclerotic lesion area. These increases were completely attenuated in HFD-KO (0.1±0.1/slice and 0.2±0.04/slice, both P ≤0.05 vs. HFD-αGC). The ratio of the F4/80-positive macrophages area to the aortic lesion area was significantly higher in HFD-αGC compared to HFD-PBS (67±4 vs. 35±2 %, P≤0.01) and this increase was completely attenuated in HFD-KO (20±3 %, P≤0.01 vs. HFD-αGC). αGC significantly increased the mRNA expression of major histocompatibility complex (MHC)-class II, IFN-γ, and MMP-2 in HFD-αGC by 1.9, 21.2, and 1.6-folds, respectively (all P≤0.05 vs. HFD-PBS), and this increase was completely attenuated in HFD-KO.
Conclusions: iNKT cells are involved in the enhancement of plaque instability via activating macrophages and up-regulation of MMP-2 in vascular tissues. Regulation of iNKT cell activation may be a novel therapeutic strategy against plaque rupture.
- © 2013 by American Heart Association, Inc.