The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis

IF 4.7 Q2 IMMUNOLOGY
Garth Blackler , James Akingbasote , Ewa Cairns , Christopher Howlett , Patti Kiser , Lillian Barra
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引用次数: 1

Abstract

Objectives

HLA-DRB1 is associated with an increased risk of cardiovascular disease in patients with rheumatoid arthritis (RA). This study aimed to determine the effect of HLA-DRB1 on atherosclerotic cardiovascular disease (ASCVD) using a novel mouse model.

Methods

Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with low density lipoprotein receptor knock-out (Ldlr−/−) mice that develop atherosclerosis when fed a high fat, high cholesterol (HFHC) diet. Male and female DR4tgLdlr−/− (n = 48), Ldlr−/− (n = 24), DR4tg (n = 24), and C57Bl/6 (B6) background (n = 24) mice were fed HFHC or regular diet (RD) for 12 weeks. Blood samples were analyzed for serum lipoproteins using a colorimetric assay. C-reactive protein (CRP) and oxidized LDL (OxLDL) were measured using ELISA. Atherosclerosis in the aortas was assessed using the lipid stain, Sudan IV. The presence of citrulline in atherosclerotic plaque was determined by immunohistochemistry.

Results

Sera low-density lipoprotein cholesterol (LDL-C) levels were higher in HFHC-fed Ldlr−/− versus DR4tgLdlr−/−-; p = 0.0056, but the aortic plaque burden and degree of citrullination in the plaque were similar for these two strains. The ratio of pro-atherogenic OxLDL to LDL levels was higher in DR4tgLdlr−/− than Ldlr−/−mice; p = 0.0017. All mice had an increase in CRP when fed a HFHC diet, most pronounced for DR4tgLdlr−/−; p = 0.0009. There were no significant sex differences for DR4tgLdlr−/− mice; however, male Ldlr−/− mice had worse atherosclerosis. B6 and DR4tg mice did not have significant elevations in serum cholesterol levels and did not develop atherosclerosis.

Conclusions

Expression of HLA-DRB1 resulted in an elevation of OxLDL and a reduction in the male bias for atherosclerosis, mimicking what is observed in RA.

Abstract Image

Abstract Image

Abstract Image

HLA-DRB1*04:01对动脉粥样硬化小鼠模型的影响
目的HLA-DRB1与类风湿性关节炎(RA)患者心血管疾病风险增加有关。本研究旨在使用一种新的小鼠模型来确定HLA-DRB1对动脉粥样硬化性心血管疾病(ASCVD)的影响。方法将HLA-DRB1*04:01(DR4tg)转基因小鼠与低密度脂蛋白受体敲除(Ldlr−/-)小鼠杂交,这些小鼠在高脂、高胆固醇(HFHC)饮食中发生动脉粥样硬化。雄性和雌性DR4tgLdlr−/−(n=48)、Ldlr–/−(n=24)、DR4tg(n=24)和C57Bl/6(B6)背景(n=24。使用比色法分析血液样本中的血清脂蛋白。采用ELISA法测定C反应蛋白(CRP)和氧化低密度脂蛋白(OxLDL)。使用脂质染色Sudan IV评估主动脉中的动脉粥样硬化。通过免疫组织化学测定动脉粥样硬化斑块中瓜氨酸的存在。结果HFHC喂养的Ldlr−/−组血清低密度脂蛋白胆固醇(LDL-C)水平高于DR4tgLdlr–/−组;p=0.0056,但这两种菌株的主动脉斑块负荷和斑块中的瓜氨酸化程度相似。DR4tgLdlr−/−小鼠的促动脉粥样硬化OxLDL与LDL水平之比高于Ldlr–/−小鼠;p=0.0017。当喂食HFHC饮食时,所有小鼠的CRP都有所增加,DR4tgLdlr−/−最为显著;p=0.0009。DR4tgLdlr−/−小鼠没有显著的性别差异;然而,雄性Ldlr−/−小鼠的动脉粥样硬化更严重。B6和DR4tg小鼠的血清胆固醇水平没有显著升高,也没有发生动脉粥样硬化。结论HLA-DRB1的表达导致OxLDL的升高和动脉粥样硬化男性偏倚的减少,这与在RA中观察到的相似。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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