Department of Clinical Biochemistry, KB3011, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.
Nephrol Dial Transplant. 2010 Aug;25(8):2486-91. doi: 10.1093/ndt/gfq059. Epub 2010 Feb 17.
Uraemia increases oxidative stress, plasma titres of antibodies recognizing oxidized low-density lipoprotein (oxLDL) and development of atherosclerosis. Immunization with oxLDL prevents classical, non-uraemic atherosclerosis. We have investigated whether immunization with oxLDL might also prevent uraemia-induced atherosclerosis in apolipoprotein E knockout (apoE-/-) mice.
ApoE-/- mice were immunized with either native LDL (n = 25), Cu(2+)-oxidized LDL (n = 25), PBS (n = 25), the apolipoprotein B-derived peptide P45 (apoB-peptide P45) conjugated to bovine serum albumin (BSA) (n = 25) or BSA (n = 25) prior to induction of uraemia by 5/6 nephrectomy (NX).
Immunization with oxLDL increased plasma titres of immunoglobulin G (IgG) recognizing Cu(2+)-oxLDL and malondialdehyde-modified LDL (MDA-LDL). However, 5/6 NX induced a marked increase in plasma concentrations of anti-oxLDL antibodies as well as pro-atherogenic cytokines [interleukin (IL)-2 (IL-2), IL-4, IL-6 and IL-12)] in native mouse LDL (nLDL)-, oxLDL- and PBS-immunized mice. Even though nLDL- and oxLDL-immunized mice displayed higher anti-MDA-LDL IgG titres than the PBS group, aortic atherosclerosis lesion size was not affected by immunization. Immunization with the apoB-peptide P45, which consistently reduces classical atherosclerosis in non-uraemic mice, also did not reduce lesion size in uraemic apoE-/- mice.
The results suggest that the pro-inflammatory and pro-atherogenic effect of uraemia overrules the anti-atherogenic potential of oxLDL immunization in apoE-/- mice.
尿毒症会增加氧化应激、血浆中识别氧化型低密度脂蛋白（oxLDL）的抗体滴度，并促进动脉粥样硬化的发展。oxLDL 免疫接种可预防经典的非尿毒症性动脉粥样硬化。我们研究了 oxLDL 免疫接种是否也能预防载脂蛋白 E 基因敲除（apoE-/-）小鼠的尿毒症诱导的动脉粥样硬化。
apoE-/-小鼠在进行尿毒症诱导（5/6 肾切除）之前，分别用天然 LDL（n = 25）、Cu（2+）-氧化 LDL（n = 25）、PBS（n = 25）、载脂蛋白 B 衍生肽 P45（apoB-peptide P45）与牛血清白蛋白（BSA）偶联物（n = 25）或 BSA（n = 25）进行免疫接种。
oxLDL 免疫接种增加了识别 Cu（2+）-oxLDL 和丙二醛修饰 LDL（MDA-LDL）的 IgG 抗体的血浆滴度。然而，5/6 NX 在天然 LDL（nLDL）、oxLDL 和 PBS 免疫接种的小鼠中引起了抗 oxLDL 抗体以及促动脉粥样硬化细胞因子[白细胞介素（IL）-2（IL-2）、IL-4、IL-6 和 IL-12]的血浆浓度的显著增加。尽管 nLDL 和 oxLDL 免疫接种的小鼠显示出比 PBS 组更高的抗 MDA-LDL IgG 滴度，但免疫接种并没有影响主动脉粥样硬化病变的大小。apoB-peptide P45 的免疫接种可一致降低非尿毒症小鼠的经典动脉粥样硬化，在尿毒症 apoE-/- 小鼠中也不能减少病变大小。
这些结果表明尿毒症的促炎和促动脉粥样硬化作用超过了 oxLDL 免疫接种在 apoE-/- 小鼠中的抗动脉粥样硬化潜力。
