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

Alexander Akhmedov, Margot Crucet, Branko Simic, Simon Kraler, Nicole R. Bonetti, Caroline Ospelt, Oliver Distler, Adrian Ciurea, Luca Liberale, Matti Jauhiainen, Jari Metso, Melroy Miranda, Rose Cydecian, Lena Schwarz, Vera Fehr, Rita Zilinyi, Mohammad Amrollahi-Sharifabadi, Lydia Ntari, Niki Karagianni, Frank RuschitzkaReijo Laaksonen, Paul M. Vanhoutte, George Kollias, Giovanni G. Camici, Thomas F. Lüscher

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)254-266
Number of pages13
JournalCARDIOVASCULAR RESEARCH
Volume118
Issue number1
DOIs
Publication statusPublished - Jan 2022
Publication typeA1 Journal article-refereed

Keywords

  • Arg2
  • Endothelium
  • LOX-1
  • TNFα
  •  Rheumatoid arthritis

Publication forum classification

  • Publication forum level 2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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