Division of Rheumatology, Harbor-UCLA Medical Center, The Lundquist Institute, Torrance, CA, USA.
Department of Food and Drug, University of Parma, Parma, Italy.
Rheumatology (Oxford). 2023 Mar 1;62(3):1254-1263. doi: 10.1093/rheumatology/keac394.
Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages.
In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM.
OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)].
Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.
巨噬细胞内胆固醇过度积累是动脉粥样硬化斑块形成的关键步骤。本研究旨在探讨类风湿关节炎（RA）患者血清中的相关因素，并探讨其与巨噬细胞胆固醇载量（CLC）相互作用及影响 CLC 的机制。
在一项包含 104 例 RA 患者的横断面观察性队列研究中，我们用人 THP-1 衍生的巨噬细胞孵育患者血清后，测量细胞内胆固醇含量来评估 CLC。用载脂蛋白 B100 所含颗粒上的氧化磷脂（oxPL-apoB100）来衡量 LDL 氧化。同时还定量了抗 oxLDL 抗体（anti-oxLDL）、前蛋白转化酶枯草溶菌素/kexin 9 型（PCSK9）和高敏 C 反应蛋白（hs-CRP）。所有分析均根据动脉粥样硬化性心血管疾病（ASCVD）风险评分、肥胖、总 LDL、他汀类药物使用、发病年龄和抗 oxLDL IgM 进行调整。
oxPL-apoB100、anti-oxLDL IgG 和 PCSK9 与 CLC 呈正相关（均 P<0.020）。仅在 RF 和 ACPA 双阳性患者中，oxPL-apoB100 直接影响 CLC [未标准化 b（95% bootstrap CI）=2.08（0.38，3.79）]。随着 CRP 水平的升高，oxPL-apoB100 通过 anti-oxLDL IgG 对 CLC 的间接影响也随之增加[中介 moderation 指数=0.55（0.05-1.17）]。CRP 还调节了 oxPL-apoB100 通过上调 PCSK9 对 CLC 的另一个间接影响，但仅在双阳性患者中如此[条件间接效应=0.64（0.13-1.30）]。
氧化 LDL 可直接影响双阳性 RA 患者的 CLC。oxPL-apoB100 可通过抗 oxLDL IgG 和 PCSK9 两条独立途径影响 CLC，这取决于 CRP 和血清学状态。如果得到外部验证，这些发现可能对心血管风险预防具有临床意义。
