Determinants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress

doi:10.1016/j.freeradbiomed.2010.06.009

Free Radical Biology and Medicine

Volume 49, Issue 5, 1 September 2010, Pages 857-864

https://doi.org/10.1016/j.freeradbiomed.2010.06.009 Get rights and content

Abstract

Thromboxane (TX) biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in rheumatoid arthritis (RA). In this study, we investigated the determinants of TX biosynthesis in RA, with particular reference to enhanced oxidative stress, receptor for advanced glycation end-products (RAGE) hyperactivity, and anti-tumor necrosis factor (TNF) treatment. Fifty-four patients with RA and 20 healthy subjects were recruited and a cross-sectional comparison of urinary 11-dehydro-TXB₂, 8-iso-PGF_2α, and plasma endogenous secretory RAGE (esRAGE) levels was performed between patients and controls. Urinary 11-dehydro-TXB₂ was significantly higher in RA patients than in healthy controls [425 (309–592) vs 233 (158–327) pg/mg creatinine, P < 0.0001]. Furthermore, urinary 8-iso-PGF_2α [323 (221–515) vs 172 (91–292) pg/mg creatinine, P < 0.0001] and plasma esRAGE [155 (100–240) vs 377 (195–486) pg/ml, P = 0.001] were higher and lower, respectively, in patients than in controls. A direct correlation was found between urinary 11-dehydro-TXB₂ and 8-iso-PGF_2α only in patients not on anti-TNF therapy (r = 0.420, P = 0.021). Conversely, patients on anti-TNF therapy showed significantly lower urinary 8-iso-PGF_2α [284 (201–373) vs 404 (241–539) pg/mg creatinine, P = 0.043] but not 11-dehydro-TXB₂ than anti-TNF-treated subjects, with esRAGE as the only independent predictor of 11-dehydro-TXB₂ in this group of patients (adjusted R² = 0.496, β = − 0.725, SEM = 0.025, P = 0.001). In conclusion, we provide biochemical evidence of enhanced TX biosynthesis in patients with RA, driven, at least in part, by lipid peroxidation. Treatment with anti-TNF agents may blunt isoprostane generation in the absence of significant effects on TX biosynthesis. We suggest that RAGE hyperactivity may escape TNF blockade, thus contributing to persistent TX biosynthesis in this setting.

Section snippets

Subjects

Fifty-four patients with RA according to the criteria of the American College of Rheumatology [27] (50 women and 4 men, mean age 55 ± 12 years; disease duration 13 ± 9 years) were recruited as outpatients of the Rheumatology Clinic of Pescara Hospital. As the control group, 20 healthy subjects (17 women and 3 men, mean age 43 ± 12 years) were also studied. Clinical features of the patients and healthy controls are detailed in Table 1.

All study patients underwent a standard clinical examination. Body

Results

Urinary 11-dehydro-TXB₂ was significantly higher in patients with RA than in control subjects [median (IQR): 425 (309–592) vs 233 (158–327) pg/mg creatinine, P < 0.0001; Fig. 1A]. Urinary 11-dehydro-TXB₂ was not significantly different in diabetic versus nondiabetic patients (P = 0.219) or in hypertensive versus normotensive subjects (P = 0.165). Moreover, patients with RA had significantly enhanced urinary excretion of 8-iso-PGF_2α compared to controls [323 (221–515) vs 172 (91–292) pg/mg creatinine,

Discussion

Epidemiological studies revealed a limited predictive value of traditional cardiovascular risk factors in RA, thus underlining the need to find reliable biomarkers of atherothrombotic risk in autoimmune inflammatory diseases [5], [6], [7].

Platelets seem to contribute to the development of atherosclerosis by secreting mediators of cell adhesion, proliferation, and inflammatory response [10].

The ex vivo measurement of platelet responses to various agonists provides an index of the functional

Acknowledgments

This research was supported by a European Commission FP6 EICOSANOX grant (LSHM-CT-2004-005033). This publication reflects only the authors’ views. The Commission is not liable for any use that may be made of information herein.

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Significance of urinary 11-dehydro-thromboxane B<inf>2</inf> in age-related diseases: Focus on atherothrombosis
2018, Ageing Research Reviews
Citation Excerpt :
CV disease largely accounts for the increased morbidity and mortality in RA (Kremers et al., 2008; Tyrrell et al., 2010). TX biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in RA (Ferrante et al., 2010) (Table 1). Urinary 11-dehydro-TXB2 is significantly higher in RA patients compared with controls (Ferrante et al., 2010; Nakamura et al., 2001); both the linear inverse dependence of 11-dehydro-TXB2 with esRAGE levels, reflecting the inflammatory RAGE axis, and the reversal of these biochemical abnormalities following anti-tumor necrosis factor (TNF)-treatment, may indicate that extraplatelet sources are likely to be involved (Ferrante et al., 2010).
Platelet activation plays a key role in atherogenesis and atherothrombosis. Biochemical evidence of increased platelet activation in vivo can be reliably obtained through non-invasive measurement of thromboxane metabolite (TXM) excretion.
Persistent biosynthesis of TXA₂ has been associated with several ageing-related diseases, including acute and chronic cardio-cerebrovascular diseases and cardiovascular risk factors, such as cigarette smoking, type 1 and type 2 diabetes mellitus, obesity, hypercholesterolemia, hyperhomocysteinemia, hypertension, chronic kidney disease, chronic inflammatory diseases.
Given the systemic nature of TX excretion, involving predominantly platelet but also extraplatelet sources, urinary TXM may reflect either platelet cyclooxygenase-1 (COX-1)–dependent TX generation or COX-2–dependent biosynthesis by inflammatory cells and/or platelets, or a combination of the two, especially in clinical settings characterized by low-grade inflammation or enhanced platelet turnover.
Although urinary 11-dehydro-TXB₂ levels are largely suppressed with low-dose aspirin, incomplete TXM suppression by aspirin predicts the future risk of vascular events and death in high-risk patients and may identify individuals who might benefit from treatments that more effectively block in vivo TX production or activity. Several disease-modifying agents, including lifestyle intervention, antidiabetic drugs and antiplatelet agents besides aspirin have been shown to reduce TX biosynthesis. Taken together, these aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis.
We intended to critically review current knowledge on both the pathophysiological significance of urinary TXM excretion in clinical settings related to ageing and atherothrombosis, as well as its prognostic value as a biomarker of vascular events.
Docosahexaenoic acid in the treatment of rheumatoid arthritis: A double-blind, placebo-controlled, randomized cross-over study with microalgae vs. sunflower oil
2018, Clinical Nutrition
Citation Excerpt :
Thromboxane A2 (or its metabolite TXB2) acts as vasoconstrictor and facilitates platelet aggregation [40]. Urinary dehydro-TXB2 levels are higher in RA patients compared to healthy controls, indicating that its biosynthesis is increased in RA patients [41]. This hypothesis is confirmed by a positive correlation between DAS28 score and serum TXB2 concentrations [42].
The potential of fish or fish oil as supplier for eicosapentaenoic acid (EPA, C20:5n3) and docosahexaenoic acid (DHA, C22:6n3) for reducing cardiovascular risk factors and supporting therapy of chronic inflammatory diseases, has been investigated intensively, but our knowledge about the physiological effects of the individual compounds EPA and DHA are limited.
In this double-blind pilot study, thirty-eight patients with defined RA were allocated to consume foods enriched with microalgae oil from Schizochytrium sp. (2.1 g DHA/d) or sunflower oil (placebo) for 10 weeks (cross-over), maintaining the regular RA medication during the study.
In contrast to placebo, the daily consumption of DHA led to a decline in the sum of tender and swollen joints (68/66) from 13.9 ± 7.4 to 9.9 ± 7.0 (p = 0.010), total DAS28 from 4.3 ± 1.0 to 3.9 ± 1.2 (p = 0.072), and ultrasound score (US-7) from 15.1 ± 9.5 to 12.4 ± 7.0 (p = 0.160).
The consumption of placebo products caused an increase of the n-6 PUFA linoleic acid and arachidonic acid (AA) in erythrocyte lipids (EL, p < 0.05). The amount of DHA was doubled in EL of DHA-supplemented patients and the ratios of AA/EPA and AA/DHA dropped significantly. We speculate that the production of pro-inflammatory/non-resolving AA-derived eicosanoids might decrease in relation to anti-inflammatory/pro-resolving DHA- and EPA-derived lipid mediators. In fact, plasma concentrations of AA-derived thromboxane B₂ and the capacity of blood to convert AA to the pro-inflammatory 5-lipoxygenase product 5-hydroxyeicosatetraenoic acid were significantly reduced, while levels of the DHA-derived maresin/resolvin precursors 14-/17-hydroxydocosahexaenoic acid significantly increased due to DHA supplementation.
The study shows for the first time that supplemented microalgae DHA ameliorates disease activity in patients with RA along with a shift in the balance of AA- and DHA-derived lipid mediators towards an anti-inflammatory/pro-resolving state.
Decreased plasma endogenous soluble RAGE, and enhanced adipokine secretion, oxidative stress and platelet/coagulative activation identify non-alcoholic fatty liver disease among patients with familial combined hyperlipidemia and/or metabolic syndrome
2015, Vascular Pharmacology
Citation Excerpt :
Furthermore, ox-LDL were analyzed within one week after collection and immediate storage at − 80 °C, in order to avoid any putative further in-vitro oxidation, as previously stated [24]. Plasma esRAGE was measured using the B-Bridge ELISA (B-Bridge International, Cupertino, CA) as previously described [25]. This assay specifically measures the esRAGE/RAGEv1 protein only, due to the use of an antibody directed against the unique COOH-terminal sequence of RAGE-v1 and does not cross-react with other potential forms of sRAGE.
In patients with familial combined hyperlipidemia (FCHL), without metabolic syndrome (MS), occurrence of non-alcoholic fatty liver disease (NAFLD) is related to a specific pro-inflammatory profile, influenced by genetic traits, involved in oxidative stress and adipokine secretion.
Among FCHL or MS patients, hyperactivity of the ligand–receptor for advanced glycation-end-products (RAGE) pathway, as reflected by inadequate protective response by the endogenous secretory (es)RAGE, in concert with genetic predisposition, may identify those with NAFLD even before and regardless of MS.
We cross-sectionally compared 60 patients with vs. 50 without NAFLD. Each group included patients with FCHL alone, MS alone, and FCHL plus MS.
NAFLD patients had significantly lower plasma esRAGE, IL-10 and adiponectin, and higher CD40 ligand, endogenous thrombin potential and oxidized LDL. The effects of MS plus FCHL were additive. The genotypic cluster including LOX-1 IVS4-14A plus ADIPO 45GG and 256 GT/GG plus IL-10 10-1082G, together with higher esRAGE levels highly discriminate FCHL and MS patients not developing NAFLD.
Among FCHL or MS patients, noncarriers of the protective genotypic cluster, with lower esRAGE and higher degree of atherothrombotic abnormalities coincide with the diagnosis of NAFLD. This suggests an interplay between genotype, adipokine secretion, oxidative stress and platelet/coagulative activation, accelerating NAFLD occurrence as a proxy for cardiovascular disease.
Platelets and diabetes mellitus
2015, Prostaglandins and Other Lipid Mediators
Platelet activation plays a key role in atherothrombosis in type 2 diabetes mellitus (T2DM) and increased in vivo platelet activation with enhanced thromboxane (TX) biosynthesis has been reported in patients with impairment of glucose metabolism even in the earlier stages of disease and in the preclinical phases. In this regards, platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. The present review critically addresses key pathophysiological aspects including (i) hyperglycemia, glycemic variability and insulin resistance as determinants and predictors of platelet activation, (ii) inflammatory mediators derived from platelets, such as soluble CD40 ligand, soluble CD36, Dickkopf-1 and probably soluble receptor for advanced glycation-end-products (sRAGE), which expand the functional repertoire of platelets from players of hemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation, and cell–cell interactions; (iii) molecular mechanisms underpinning the less-than-expected antithrombotic protection by aspirin (ASA), despite regular antiplatelet prophylaxis at the standard dosing regimen, and (iv) stratification of patients deserving different antiplatelet strategies, based on the metabolic phenotype. Taken together, these pathophysiological aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis in diabetic subjects.
The cyclooxygenase-2/thromboxane A2 pathway: a bridge from rheumatoid arthritis to lung cancer?
2014, Cancer Letters
Citation Excerpt :
The observation of these adverse effects led to the withdrawal of rofecoxib and valdecoxib from the American market, in 2004 and 2005, respectively. In addition, the newest anti-TNF-α agents, which lack significant effects on TxA2 biosynthesis [42], have been associated with a higher frequency of non-melanoma skin cancer in RA patients [52]. Along with NSAIDs, disease-modifying antirheumatic drugs (DMARDs) currently remain the gold standard pharmacological therapy for RA.
Patients with rheumatoid arthritis (RA) appear to be at a higher risk of lung cancer (LC). Although the connection between RA and LC has been an active area of research for many years, the molecular pathogenesis of the disease process remains unclear. The cyclooxygenase (COX)-2/thromboxane A2 (TxA2) pathway has been shown to play a potential role in LC development through an auto-regulatory feedback loop. An increased level of TxA2 has been found in RA patients, and intriguingly, the positive feedback loop for the COX-2/TxA2 pathway was shown to have a potential function in RA fibroblast-like synoviocytes (RA-FLS). Thus, the molecular basis of LC development in patients with RA has been at least in partly described. It is possible that COX-2-derived TxA2 could be monitored for the early detection of LC in RA patients, and targeting this molecular pathway may decrease the risk of LC in patients with RA.
Advanced oxidation protein products induce inflammatory responses and invasive behaviour in fibroblast-like synoviocytes via the RAGE-NFκB pathway
2021, Bone and Joint Research

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Original ContributionDeterminants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress

Abstract

Section snippets

Subjects

Results

Discussion

Acknowledgments

Blood

Curr. Opin. Pharmacol.

Biochim. Biophys. Acta

Prostaglandins Leukotrienes. Essent. Fatty Acids

Am. J. Med.

High ten-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: A population-based cohort study

Arthritis Rheum.

Rheumatic disease and carotid intima-media thickness: A systematic review and meta-analysis

Arterioscler. Thromb. Vasc. Biol.

Atherosclerosis in rheumatoid arthritis versus diabetes: A comparative study

Arterioscler. Thromb. Vasc. Biol.

Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study

Arthritis Rheum.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

Arthritis Rheum.

Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients?

Ann. Rheum. Dis.

Rheumatic diseases: Insights into inflammation and atherosclerosis

Arterioscler. Thromb. Vasc. Biol.

Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis

Circulation

Inflamed joints and stiff arteries: Is rheumatoid arthritis a cardiovascular risk factor?

Circulation

Platelet activation and atherothrombosis

N. Engl. J. Med.

Oxidant stress, inflammation and atherogenesis

Lupus

Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis

Curr. Med. Chem.

Platelet expression of tumour necrosis factor-alpha (TNF-alpha), TNF receptors and intercellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy

Clin. Exp. Immunol.

The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

J. Clin. Invest.

How RAGE turns in rage

Genes Immun.

Soluble forms of RAGE in human diseases: Clinical and therapeutical implications

Curr. Med. Chem.

Soluble forms of RAGE in internal medicine

Intern. Emerg. Med.

Original Contribution
Determinants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress