ArticleArthritis research & therapy2006
Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis.
Article in Arthritis research & therapy, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 39 citations in OpenAlex.
- Statins Restore Endothelial Protection against Complement Activity in Obstructive Sleep Apnea: A Randomized Clinical Trial.Annals of the American Thoracic Society · 2023Trial
- Molecular and Immunomodulatory Mechanisms of Statins in Inflammation and Cancer Therapeutics with Emphasis on the NF-κB, NLRP3 Inflammasome, and Cytokine Regulatory Axes.International journal of molecular sciences · 2025Review
- Enhanced retinal pigment epithelial cells as a delivery vehicle for retinal disease.Molecular therapy. Methods & clinical development · 2025Article
- Disparities in statin use in patients with ASCVD with vs without rheumatologic diseases in a large integrated healthcare system: Houston methodist CVD learning health system registry.American journal of preventive cardiology · 2025Article
- Canonical and non-canonical roles of complement in atherosclerosis.Nature reviews. Cardiology · 2024Review
- Association of Blood Group Antigen CD59 with Disease.Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie · 2022Review
- Targeting the complement system in neuromyelitis optica spectrum disorder.Expert opinion on biological therapy · 2021Review
- Exosomes derived from synovial fibroblasts under hypoxia aggravate rheumatoid arthritis by regulating Treg/Th17 balance.Experimental biology and medicine (Maywood, N.J.) · 2020Article
- Hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants.Journal of translational medicine · 2020Article
- The complement system in primary Sjögren's syndrome: the expression of certain cascade and regulatory proteins in labial salivary glands - observational study.Reumatologia · 2020Article
- CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica.Journal of neuroinflammation · 2019Article
- Altered Expression of Complement Regulatory Proteins CD35, CD46, CD55, and CD59 on Leukocyte Subsets in Individuals Suffering From Coronary Artery Disease.Frontiers in immunology · 2019Article
- Peripheral tolerance can be modified by altering KLF2-regulated Treg migration.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Evaluation of the Anti-inflammatory Effects of Atorvastatin on Patients with Rheumatoid Arthritis: A Randomized Clinical Trial.Electronic physician · 2016Article
- Increased internalization of complement inhibitor CD59 may contribute to endothelial inflammation in obstructive sleep apnea.Science translational medicine · 2016Article
- Shiga toxin 2 reduces complement inhibitor CD59 expression on human renal tubular epithelial and glomerular endothelial cells.Infection and immunity · 2013Article
- Article
- The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review.Rheumatology international · 2012Review
- Statins impair antitumor effects of rituximab by inducing conformational changes of CD20.PLoS medicine · 2008Article
- Statins and the vascular endothelial inflammatory response.Trends in immunology · 2007Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis (RA). Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation. Flow-cytometric analysis showed that CD59 expression on endothelial cells (EC) was unaffected by atorvastatin in normoxia (21% O2), whereas in hypoxic conditions (1% O2) an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor (DAF), is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.
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