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

Cardiovasc Res. 2022 Jan 7;118(1):254-266. doi: 10.1093/cvr/cvab005.


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.

Keywords: Arg2; Endothelium; LOX-1; TNFα; Rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Animals, Genetically Modified
  • Aorta, Thoracic / drug effects*
  • Aorta, Thoracic / enzymology
  • Aorta, Thoracic / immunology
  • Aorta, Thoracic / physiopathology
  • Arginase / genetics
  • Arginase / metabolism*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / physiopathology
  • Case-Control Studies
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / immunology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • Lipoproteins, LDL / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Middle Aged
  • NF-kappa B / metabolism
  • Scavenger Receptors, Class E / genetics
  • Scavenger Receptors, Class E / metabolism*
  • Signal Transduction
  • Tumor Necrosis Factor Inhibitors / therapeutic use*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vasodilation / drug effects*


  • Lipoproteins, LDL
  • NF-kappa B
  • OLR1 protein, human
  • Olr1 protein, mouse
  • Scavenger Receptors, Class E
  • TNF protein, human
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha
  • oxidized low density lipoprotein
  • ARG2 protein, human
  • Arg2 protein, mouse
  • Arginase