炎症和免疫调节疗法影响atp结合盒A1膜转运体介导的胆固醇外排能力与类风湿关节炎冠状动脉粥样硬化之间的关系

IF 4.7 Q2 IMMUNOLOGY Journal of Translational Autoimmunity Pub Date : 2023-07-18 DOI:10.1016/j.jtauto.2023.100209
George A. Karpouzas , Bianca Papotti , Sarah R. Ormseth , Marcella Palumbo , Elizabeth Hernandez , Maria Pia Adorni , Francesca Zimetti , Matthew J. Budoff , Nicoletta Ronda
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引用次数: 0

摘要

目的:高密度脂蛋白(HDL)可清除动脉粥样硬化病变细胞中的胆固醇,这种功能被称为胆固醇外排能力(CEC)。atp结合盒A1 (ABCA1)膜转运蛋白启动胆固醇从巨噬细胞向HDL颗粒的转移。在类风湿性关节炎(RA)中,甲氨蝶呤和生物疾病修饰药物(bDMARDs)具有动脉粥样硬化保护作用,而皮质类固醇和c反应蛋白(CRP)具有动脉粥样硬化促生作用。我们评估了这些因素对ABCA1-CEC与动脉粥样硬化和心血管事件的关系的影响。方法对140例RA患者行ct血管造影检查,99例患者术后6.9±0.3年复查。事件包括急性冠状动脉综合征、中风、心血管死亡、跛行、血运重建术和心力衰竭。在J774A中定量ABCA1-CEC。1小鼠巨噬细胞,以细胞内胆固醇外排百分比报告。结果较高的ABCA1-CEC与(1)基线时较多钙化斑块仅与CRP>7 mg/L(中位数)(p-相互作用= 0.001)和未使用甲氨蝶呤(p-相互作用= 0.037)的患者相关,仅与未使用bDMARD的患者相关(p-相互作用= 0.029);(ii)低于中位数但时间平均CRP不高的患者新发钙化斑块较少(p-相互作用= 0.028);(iii)在随访期间,未暴露于强的松但暴露于强的松的患者中新出现的总斑块和钙化斑块较少(p-相互作用= 0.034和0.004);(iv)基线bDMARD未使用者中新出现的斑块较多,bDMARD使用者中新出现的斑块较少(p-相互作用≤0.001)。此外,ABCA1-CEC仅与基线强的松使用者的心血管风险增加相关(p交互作用= 0.027)。结论:在使用低于中位基线和时间平均CRP和bDMARD的患者中,abca1 - cec与动脉粥样硬化减少相关。相反,在高CRP、皮质类固醇使用者、甲氨蝶呤非使用者和bDMARD非使用者中,ABCA1-CEC与斑块增加相关。虽然在治疗良好和控制的疾病中,ABCA1-CEC表现出动脉粥样硬化保护作用,但在不受控制的RA中,ABCA1-CEC的作用可能被掩盖或无法抵消炎症驱动的促动脉粥样硬化状态。
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Inflammation and immunomodulatory therapies influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis

Objectives

High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events.

Methods

Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol.

Results

Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027).

Conclusion

ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

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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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