Sera from Rheumatoid Arthritis Patients Induce Oxidative Stress and Pro-Angiogenic and Profibrotic Phenotypes in Human Endothelial Cells

Overview

Journal J Clin Med

Specialty General Medicine

Date 2024 Oct 16

PMID 39407973

Authors

Roberta Giordo

Anna Maria Posadino

Paola Maccioccu

Giampiero Capobianco

Angelo Zinellu

Gian Luca Erre

Gianfranco Pintus

Affiliations

Soon will be listed here.

Abstract

Rheumatoid arthritis (RA) is a long-term autoimmune condition marked by persistent inflammation of the joints and various systemic complications, including endothelial dysfunction, atherosclerosis, and pulmonary fibrosis. Oxidative stress is a key contributor to the pathogenesis of RA, potentially exacerbating vascular damage and promoting pro-angiogenic and profibrotic processes. This study aims to investigate the effects of sera from RA patients on human umbilical vein endothelial cells (HUVECs), focusing on the induction of oxidative stress, endothelial cell proliferation, migration, and collagen type I synthesis. Twenty-eight serum samples were collected from RA patients and healthy donors (HDs). HUVECs were exposed to these sera, and intracellular reactive oxygen species (ROS) levels were fluorescently detected using H2DCF-DA. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell migration was evaluated through a scratch wound assay, and collagen type I synthesis was measured using a lentiviral vector expressing the green fluorescent protein (GFP) under the control of the human COL1A1 gene promoter. Exposure to RA sera resulted in a significant increase in intracellular ROS levels in HUVECs compared to HD sera, indicating an elevated state of oxidative stress. RA sera also promoted endothelial cell proliferation and migration, suggesting a pro-angiogenic stimulus. Additionally, RA sera significantly increased collagen type I synthesis in HUVECs, implicating a potential role in profibrotic processes associated with RA. The results of this study emphasize the importance of circulating factors in RA sera in promoting oxidative stress, endothelial dysfunction, and pro-angiogenic and profibrotic phenotypes in endothelial cells. These processes may contribute to the vascular and fibrotic complications observed in RA, highlighting the necessity for additional research into focused therapeutic approaches to alleviate these effects.

References

Lopez-Armada M, Fernandez-Rodriguez J, Blanco F . Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis. Antioxidants (Basel). 2022; 11(6). PMC: 9220001. DOI: 10.3390/antiox11061151. View

Bo M, Erre G, Bach H, Slavin Y, Manchia P, Passiu G . PtpA and PknG Proteins Secreted by subsp. are Recognized by Sera from Patients with Rheumatoid Arthritis: A Case-Control Study. J Inflamm Res. 2019; 12:301-308. PMC: 6899068. DOI: 10.2147/JIR.S220960. View

Djordjevic K, Milojevic Samanovic A, Veselinovic M, Zivkovic V, Mikhaylovsky V, Mikerova M . Oxidative Stress Mediated Therapy in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. Antioxidants (Basel). 2023; 12(11). PMC: 10669381. DOI: 10.3390/antiox12111938. View

Bordy R, Totoson P, Prati C, Marie C, Wendling D, Demougeot C . Microvascular endothelial dysfunction in rheumatoid arthritis. Nat Rev Rheumatol. 2018; 14(7):404-420. DOI: 10.1038/s41584-018-0022-8. View

McKleroy W, Lee T, Atabai K . Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. Am J Physiol Lung Cell Mol Physiol. 2013; 304(11):L709-21. PMC: 3680761. DOI: 10.1152/ajplung.00418.2012. View

Quinonez-Flores C, Gonzalez-Chavez S, Del Rio Najera D, Pacheco-Tena C . Oxidative Stress Relevance in the Pathogenesis of the Rheumatoid Arthritis: A Systematic Review. Biomed Res Int. 2016; 2016:6097417. PMC: 4906181. DOI: 10.1155/2016/6097417. View

Shaito A, Aramouni K, Assaf R, Parenti A, Orekhov A, Yazbi A . Oxidative Stress-Induced Endothelial Dysfunction in Cardiovascular Diseases. Front Biosci (Landmark Ed). 2022; 27(3):105. DOI: 10.31083/j.fbl2703105. View

Boin F, Erre G, Posadino A, Cossu A, Giordo R, Spinetti G . Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension. Orphanet J Rare Dis. 2014; 9:123. PMC: 4237898. DOI: 10.1186/s13023-014-0123-7. View

Elshabrawy H, Chen Z, Volin M, Ravella S, Virupannavar S, Shahrara S . The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 2015; 18(4):433-48. PMC: 4879881. DOI: 10.1007/s10456-015-9477-2. View

10.

Giordo R, Cossu A, Porcu M, Cappuccinelli R, Biosa G, Sharifi-Rad J . Cytoprotective, antioxidant, and anti-migratory activity of . supercritical carbon dioxide extract on primary human endothelial cells. Nat Prod Res. 2022; 37(16):2681-2687. DOI: 10.1080/14786419.2022.2130304. View

11.

Bassu S, Zinellu A, Sotgia S, Mangoni A, Floris A, Farina G . Oxidative Stress Biomarkers and Peripheral Endothelial Dysfunction in Rheumatoid Arthritis: A Monocentric Cross-Sectional Case-Control Study. Molecules. 2020; 25(17). PMC: 7504109. DOI: 10.3390/molecules25173855. View

12.

Vono R, Fuoco C, Testa S, Pirro S, Maselli D, Ferland McCollough D . Activation of the Pro-Oxidant PKCβII-p66Shc Signaling Pathway Contributes to Pericyte Dysfunction in Skeletal Muscles of Patients With Diabetes With Critical Limb Ischemia. Diabetes. 2016; 65(12):3691-3704. DOI: 10.2337/db16-0248. View

13.

Zhao W, Wang L, Wang Y, Yuan H, Zhao M, Lian H . Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis. Int J Mol Sci. 2023; 24(10). PMC: 10218114. DOI: 10.3390/ijms24108749. View

14.

Datta S, Kundu S, Ghosh P, De S, Ghosh A, Chatterjee M . Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis. Clin Rheumatol. 2014; 33(11):1557-64. DOI: 10.1007/s10067-014-2597-z. View

15.

Ogita H, Liao J . Endothelial function and oxidative stress. Endothelium. 2004; 11(2):123-32. DOI: 10.1080/10623320490482664. View

16.

Diesler R, Cottin V . Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies. Expert Rev Respir Med. 2022; 16(5):541-553. DOI: 10.1080/17476348.2022.2089116. View

17.

Erre G, Bosincu L, Faedda R, Fenu P, Masala A, Sanna M . Antiphospholipid syndrome nephropathy (APSN) in patients with lupus nephritis: a retrospective clinical and renal pathology study. Rheumatol Int. 2013; 34(4):535-41. DOI: 10.1007/s00296-013-2900-3. View

18.

Posadino A, Cossu A, Giordo R, Zinellu A, Sotgia S, Vardeu A . Coumaric acid induces mitochondrial damage and oxidative-mediated cell death of human endothelial cells. Cardiovasc Toxicol. 2013; 13(3):301-6. DOI: 10.1007/s12012-013-9205-3. View

19.

Hitchon C, El-Gabalawy H . Oxidation in rheumatoid arthritis. Arthritis Res Ther. 2004; 6(6):265-78. PMC: 1064874. DOI: 10.1186/ar1447. View

20.

Firestein G . Evolving concepts of rheumatoid arthritis. Nature. 2003; 423(6937):356-61. DOI: 10.1038/nature01661. View