TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal bymonoclonal TNFα antibodies
TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal bymonoclonal TNFα antibodies
复制标题
TNFα通过LOX-1和脂酶2诱导类风湿关节炎内皮功能障碍：TNFα单克隆抗体逆转
DOI：
10.1093/cvr/cvab005
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发表时间：
2022-01-01
影响因子：
10.8
通讯作者：
Luescher, Thomas F.
中科院分区：
文献类型：
--
作者：
Akhmedov, Alexander;Crucet, Margot;Luescher, Thomas F.
风湿性关节炎（RA）是一种累及关节和血管的慢性炎症性疾病。尽管低密度脂蛋白胆固醇（LDL-C）水平较低，但RA患者仍表现出内皮功能障碍，并因心血管并发症而死亡的风险增加，但其分子作用机制尚不清楚。本研究的目的是确定RA小鼠模型和RA患者内皮功能障碍的分子机制。方法和结果在两种肿瘤坏死因子-α的诱导下，（TNF α）转基因小鼠系与轻度（Tg 3647）或重度（Tg 197）形式的RA在时间-和严重程度-器官室肌电描记器评估的依赖方式。在Tg 197中，TNF α血浆水平与重度内皮功能障碍相关。LOX-1受体显著上调，导致血管oxLDL摄取增加，NF κ B介导的Arg 2表达通过直接结合其启动子而增强，导致NO生物利用度和血管cGMP水平降低，如ELISA和染色质免疫沉淀所示。用英夫利西单抗抗治疗使小鼠的内皮功能以及LOX-1和Arg 2血清水平正常化。在RA患者中，可溶性LOX-1血清水平也明显升高，并与血清C反应蛋白水平密切相关。同样，ARG 2血清水平升高。同样，抗TNF α治疗恢复LOX-1和ARG 2血清水平在RA patients.Conclusions增加TNF α水平不仅有助于RA，但也通过增加血管oxLDL含量和激活LOX-1/NF κ B B/Arg 2途径导致内皮功能障碍降低NO生物利用度和降低cGMP水平。抗TNF α治疗通过降低LOX-1、血管oxLDL和Arg 2水平改善了关节症状和内皮功能。
Aims Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and blood vessels. Despite low levels of low-density lipoprotein cholesterol (LDL-C), RA patients exhibit endothelial dysfunction and are at increased risk of death from cardiovascular complications, but the molecular mechanism of action is unknown. We aimed in the present study to identify the molecular mechanism of endothelial dysfunction in a mouse model of RA and in patients with RA.Methods and results Endothelium-dependent relaxations to acetylcholine were reduced in aortae of two tumour necrosis factor alpha (TNF alpha) transgenic mouse lines with either mild (Tg3647) or severe (Tg197) forms of RA in a time- and severity-dependent fashion as assessed by organ chamber myograph. In Tg197, TNF alpha plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly up-regulated leading to increased vascular oxLDL uptake and NF kappa B-mediated enhanced Arg2 expression via direct binding to its promoter resulting in reduced NO bioavailability and vascular cGMP levels as shown by ELISA and chromatin immunoprecipitation. Anti-TNF alpha treatment with infliximab normalized endothelial function together with LOX-1 and Arg2 serum levels in mice. In RA patients, soluble LOX-1 serum levels were also markedly increased and closely related to serum levels of C-reactive protein. Similarly, ARG2 serum levels were increased. Similarly, anti-TNF alpha treatment restored LOX-1 and ARG2 serum levels in RA patients.Conclusions Increased TNF alpha levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NF kappa B/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNF alpha treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL, and Arg2 levels.