TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFα antibodies

Abstract

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 (TNFα) 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, TNFα plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly up-regulated leading to increased vascular oxLDL uptake and NFκB-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-TNFα 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-TNFα treatment restored LOX-1 and ARG2 serum levels in RA patients. Conclusions Increased TNFα levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NFκB/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNFα treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL, and Arg2 levels.

Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction

“…Our in vivo and vitro studies confirmed the results and further demonstrated that HCQ could reduce the expression of cytokines, chemokines, and adhesion molecules in uveitic retinas and TNF-a-stimulated inflammation of RVECs. Our findings are in accordance with previous studies on other kinds of endothelial cells, which represent the pathophysiology of different diseases, like atherosclerosis, coronary heart disease, rheumatoid arthritis, and diabetes mellitus (36,37). To conclude, the above results suggest that HCQ may be a promising molecule for treatment of inflammatory vascular diseases owing to its immunomodulatory effects.…”

The Impact of Cytokines in Coronary Atherosclerotic Plaque: Current Therapeutic Approaches

“…Etanercept prevented TNF-induced endothelial cell apoptosis by enhancing the process of autophagy [209]. Moreover, infliximab reversed TNF-α induced endothelial dysfunction as well as the increase in oxLDL, LOX-1, and Arg2 [210]. We have also shown that adalimumab could improve endothelial function and inflammation in patients with psoriasis [211].…”

Anemia in elderly rheumatoid arthritis patients: a cohort study

“…As a possible abnormal index of anemia in elderly patients with RA, PLR and hs-CRP have no significant correlation with the increase of immunoglobulin, while hs-CRP, as an important indicator of inflammatory response in the early stage of RA, and LDL-C and TC as important monitoring indexes of abnormal lipid metabolism, can better reflect the possibility of atherosclerosis [29,30]. Therefore, anemia in elderly patients with RA is closely related to lipid metabolism and inflammatory reaction [31][32][33]. In clinical treatment one should pay close attention to lipid metabolism and inflammation in RA patients.…”