Abstract 1489: MHCII-Deficiency Attenuates the Development of Atherosclerosis in LDLR−/−Mice
In the current study, we investigated the importance of MHCII-TCR interactions in atherosclerosis development and progression. Therefore, MHCII−/−/LDLR−/− mice were generated and fed a high fat diet for 9 weeks. FACS analysis of blood, spleen and lymph nodes confirmed MHCII deficiency and demonstrated a >30% reduced CD4+ Th-cell population in LDLR−/−/MHCII−/−mice. High fat feeding increased cholesterol and triglyceride levels in LDLR−/−/MHCII−/− mice, but significantly less than in their LDLR−/− littermates (cholesterol: 643±85 mg/dl LDLR−/−MHCII−/− vs. 1,214±217 mg/dl LDLR-/; p<0.05 and triglycerides 59±10 mg/dl LDLR−/−/MHCII−/− vs. 283±85 mg/dl LDLR−/−; p<0.05). Moreover, plasma HDL levels were increased in LDLR−/−/MHCII−/− mice (12.5% LDLR−/−/MHCII−/− vs 1.3% LDLR−/−), whereas VLDL levels had decreased (47.7% vs 68.0%). Analysis of the aortic root revealed that lesion severity was markedly attenuated in LDLR−/−/MHCII−/− mice (early lesions: 58% LDLR−/−MHCII−/− vs. 11 %, LDLR−/−; intermediate lesions 25% LDLR−/− MHCII−/− vs 25% LDLR−/−; advanced lesions: 17% LDLR−/−/MHCII−/− vs. 63% LDLR−/−; p<0.05) and that total plaque area was reduced by 64% (82,680±18,810 μm2 LDLR−/−/MHCII−/− vs. 230,200±39,530 μm2 LDLR−/−, p<0.05). A correlation of the cholesterol level with the total plaque area showed that the cholesterol level could explain only 54.7 % of the decrease in total plaque area. Further phenotypic analysis of the atherosclerotic lesions of LDLR−/−/MHCII−/− mice showed that plaques had a significantly reduced lipid core content (2.5±1.5% LDLR−/−/MHCII−/− vs. 17.6±4.1% LDLR−/−; p<0.05) and macrophage content: (71.8±4.6% LDLR−/−MHCII−/− vs. 49.2±2.8% LDLR−/−; p<0.05), and contained much fewer CD4+ cells (0.3±0.1×10−4μm−2, LDLR−/−MHCII−/− vs. 0.7±0.1×10−4μm−2 LDLR−/−, p<0.05). Impairment of the Th-cell response was confirmed by a reduced anti-MDA-LDL IgG antibody response. These data show that MHCII deficiency hampers the Th-cell response in the development and progression of atherosclerosis and decreases serum lipid levels which reduce lesion severity and atherosclerosis extent.