Blackler Garth, Akingbasote James, Cairns Ewa, Howlett Christopher, Kiser Patti, Barra Lillian
Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
Department of Medicine, Division of Rheumatology, Western University, London, Ontario, Canada.
J Transl Autoimmun. 2023 Jun 21;7:100203. doi: 10.1016/j.jtauto.2023.100203. eCollection 2023 Dec.
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.
Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with low density lipoprotein receptor knock-out () mice that develop atherosclerosis when fed a high fat, high cholesterol (HFHC) diet. Male and female DR4tg (n = 48), (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.
Sera low-density lipoprotein cholesterol (LDL-C) levels were higher in HFHC-fed versus DR4tg; 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 DR4tg than mice; p = 0.0017. All mice had an increase in CRP when fed a HFHC diet, most pronounced for DR4tg; p = 0.0009. There were no significant sex differences for DR4tg mice; however, male mice had worse atherosclerosis. B6 and DR4tg mice did not have significant elevations in serum cholesterol levels and did not develop atherosclerosis.
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.
HLA - DRB1与类风湿关节炎（RA）患者心血管疾病风险增加有关。本研究旨在使用一种新型小鼠模型确定HLA - DRB1对动脉粥样硬化性心血管疾病（ASCVD）的影响。
将携带HLA - DRB1*04:01的转基因小鼠（DR4tg）与低密度脂蛋白受体敲除小鼠（在喂食高脂肪、高胆固醇（HFHC）饮食时会发生动脉粥样硬化）进行杂交。将雄性和雌性DR4tg小鼠（n = 48）、小鼠（n = 24）、DR4tg小鼠（n = 24）和C57Bl/6（B6）背景小鼠（n = 24）喂食HFHC或常规饮食（RD）12周。使用比色法分析血样中的血清脂蛋白。使用酶联免疫吸附测定法测量C反应蛋白（CRP）和氧化低密度脂蛋白（OxLDL）。使用苏丹IV脂质染色评估主动脉中的动脉粥样硬化。通过免疫组织化学确定动脉粥样硬化斑块中瓜氨酸的存在。
喂食HFHC的小鼠血清低密度脂蛋白胆固醇（LDL - C）水平高于DR4tg小鼠；p = 0.0056，但这两种品系的主动脉斑块负担和斑块中的瓜氨酸化程度相似。DR4tg小鼠中促动脉粥样硬化的OxLDL与LDL水平之比高于小鼠；p = 0.0017。所有小鼠在喂食HFHC饮食时CRP均升高，DR4tg小鼠最为明显；p = 0.0009。DR4tg小鼠没有明显的性别差异；然而，雄性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。
HLA - DRB1的表达导致OxLDL升高，并减少了动脉粥样硬化的雄性偏向，这与在RA中观察到的情况相似。
