Phosphorylcholine (PC) is an oxidation-specific epitope present on oxidized LDL and apoptotic cells, as well as the capsular polysaccharide of Streptococcus pneumoniae. PC is bound by naturally... Show morePhosphorylcholine (PC) is an oxidation-specific epitope present on oxidized LDL and apoptotic cells, as well as the capsular polysaccharide of Streptococcus pneumoniae. PC is bound by naturally occurring IgM antibodies and low levels of anti-PC IgM are a risk factor for atherosclerosis. Active immunization of atherosclerosis-prone mice with oxidized LDL, S. pneumoniae or PC conjugated to keyhole lympet hemocyanin (PC-KLH) induces high titers of anti-PC Abs and protects from atherosclerosis. However, it is unknown if existing vaccine preparations can be exploited as preventive vaccine in atherosclerosis. Our aim was to evaluate the potential atheroprotective effect of Prevenar®, a clinical-grade pneumococcal vaccine.Male apolipoprotein E-/-,mice (n=10 per group) were injected subcutaneously with 50μl Prevenar® (diluted 1:10 in PBS) at 8 and 12 weeks of age. PC-KLH and PBS were used as positive and negative controls, respectively. Mice were fed regular chow for the entire study. Serum anti-PC Abs were analyzed at baseline and 15 days after the second injection. After 20 weeks serum lipid levels were measured and atherosclerotic lesion size was quantified in the aortic root.Both vaccination with Prevenar® and PC-KLH induced high titers of anti-PC IgM and IgG Abs and resulted in reduced atherosclerosis compared to PBS injected mice (figure) despite similar serum cholesterol levels.The amount of residual PC in Prevenar® is sufficient to elicit atheroprotective anti-PC responses in apoE-/- mice. Since Prevenar® is already used in humans, its potential to prevent atherosclerosis and/or slow down atherosclerosis progression could readily be tested in clinical trials. Show less
Snip, O.S.C.; Hoekstra, M.; Zhao, Y.; Calpe-Berdiel, L.; Vulve, J.; Carles Escola-Gil, J.; ... ; Eck, M. van 2018
Various studies have shown that leukocyteATP-binding cassette transporter A1 (ABCA1) is an anti-atherogenic factor. It has long been assumed that the increased atherosclerosis susceptibility... Show moreVarious studies have shown that leukocyteATP-binding cassette transporter A1 (ABCA1) is an anti-atherogenic factor. It has long been assumed that the increased atherosclerosis susceptibility observed in leukocyte ABCA1 deficient hyperlipidemic mice was due to an accelerated foam cell formation. However, several studies have suggested that leukocyte ABCA1 may also have a beneficial effect on systemic inflammation. In this study we aim to determine the effect of leukocyte ABCA1 deficiency on atherosclerosis susceptibility in mice that are apolipoprotein A1 (apoA1) deficient.To determine the impact of leukocyte ABCA1 on atherosclerosis outcome, lethally irradiated low-density lipoprotein receptorknock-out (sKO) mice or LDLr/apoA1 double KO (dKO) mice were reconstituted with either ABCA1 KO or wild-type bone marrow. All four groups of chimeric mice were fed a Western-type diet for 6 weeks to induce atherosclerotic lesion development.Leukocyte ABCA1 deficiency in dKO mice resulted in 50-70% larger lesions in the aortic root than those observed in both sKO mice transplanted with ABCA1 KO bone marrow and dKO mice transplanted with wild-type bone marrow. Furthermore, total leukocyte numbers in blood were generally higher in mice lacking apoA1 as compared to those containing apoA1-carrying HDL particles. Two way ANOVA on the different white blood cell sub-populations suggested that the apoA1 deficiency-associated increase in total leukocyte counts was driven by an increase in the number of lymphocytes (P<0.001) and, to a minor extent, monocytes (P<0.01).This study shows that reduced systemic inflammation and increased reverse cholesterol transport together drive macrophage ABCA1-mediated protection against atherosclerosis. Show less
