Abstract 3613: Leukocyte Nfatp Deficiency Deteriorates Rather than Protects Against Atherosclerosis
NFATp is a transcriptional factor that regulates cytokines and other genes during immune responses. Mice lacking NFATp displayed splenomegaly, allergic phenotype and increased production of TH2 cytokines in vivo and in vitro. Although intervention in the calcineurin-NFAT pathway by FK506 was earlier shown to be atheroprotective, limited data is available on the role of NFATp in atherosclerosis formation. Here we investigated the role of leukocyte NFATp deficiency in atherosclerosis. NFATp−/− or WT (C57Bl6/SV129) bone marrow was transplanted into irradiated LDLR−/− mice that were fed a cholesterol diet. Advanced lesion area in the aortic arch was increased in NFATp−/− chimeras (1.8 ± 0.2 *105 μm2, vs 1.4 ± 0.1 * 105 μm2 for WT; p<0.05) as was the percentage of advanced lesions (95.0% vs 87.6% for WT; p<0.05). Plaque CD3+ T cell content were sharply increased in NFATp−/− chimeras (0.0094 ± 0.0010% vs 0.0036 ± 0.0021% for WT; p< 0.01). However, lipid core size, collagen content, macrophage and leukocytes in lesions were not different between the two groups.Interestingly, calcification as characterized by the presence of chondrocytes markedly increased with NFATp deficiency (20.13% vs 6.47% for WT; p<0.05 ). In keeping with the higher plaque T-cell content, NFATp deficiency significantly increased the percentage of CD8+ T cells in spleen (2.4 ± 0.3 % vs 1.4 ± 0.1 % for WT) and lymph node (4.1 ± 0.5 % vs 2.7 ± 0.3 % for WT) (both p<0.05). In addition, NFATp deficiency considerably enhanced myeloid cell population of GR1+/MAC1+ granulocytes (20.2 ± 2.9 % vs 10.1 ± 1.9 %; for WT; p<0.05 ) and GR-/MAC1+ monocytes (9.3 ± 1.8 % vs 5.2 ± 0.7 % for WT; p<0.05) in blood, suggesting a hyperinflammatory status. IL-6, IL-10, IFN-γ and IL-12 in serum were not different between the two groups. We demonstrate that leukocyte NFATp is critical for atherosclerosis progression as its deficiency, contrary to our expectations, increased advanced lesion size and boosted the immunologic activity as represented by recruitment CD3+ T cells into the lesion area and an increased CD8+ T cell number and myeloid cell population systemically. Pro-active studies are currently ongoing to pinpoint effects of NFATp deficiency on regulatory T-cell function.