Alexander Akhmedov1, Margot Crucet1, Branko Simic1, Simon Kraler1, Nicole R Bonetti1, Caroline Ospelt2, Oliver Distler2, Adrian Ciurea2, Luca Liberale1,3, Matti Jauhiainen4, Jari Metso4, Melroy Miranda1, Rose Cydecian1, Lena Schwarz1, Vera Fehr1, Rita Zilinyi5, Mohammad Amrollahi-Sharifabadi1, Lydia Ntari6, Niki Karagianni6, Frank Ruschitzka7, Reijo Laaksonen8,9, Paul M Vanhoutte10, George Kollias6, Giovanni G Camici1,11, Thomas F Lüscher1,12. 1. Center for Molecular Cardiology, Schlieren Campus, University of Zurich, 8001 Zurich, Switzerland. 2. Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland. 3. Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy. 4. Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland. 5. Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary. 6. Institute for Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece. 7. Department of Cardiology, University Heart Center, University Hospital, Zürich, Switzerland. 8. Zora Biosciences Oy, Espoo, Finland. 9. Finnish Cardiovascular Research Center, University of Tampere and Finnish Clinical Biobank Tampere, Tampere University Hospital, Tampere, Finland. 10. Department of Pharmacology, Hong Kong University, Hong Kong, Peoples Republic of China. 11. Department of Research and Education, University Hospital Zurich, Zurich, Switzerland. 12. Royal Brompton and Harefield Hospitals and Imperial College, London, UK.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.