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

https://doi.org/10.1016/j.freeradbiomed.2010.06.009Get 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, 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 [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 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 [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 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.

References (44)

  • A. Gonzalez et al.

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

    Ann. Rheum. Dis.

    (2008)
  • J. Frostegård

    Rheumatic diseases: Insights into inflammation and atherosclerosis

    Arterioscler. Thromb. Vasc. Biol.

    (2010)
  • N. Sattar et al.

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

    Circulation

    (2003)
  • A.A. Quyyumi

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

    Circulation

    (2006)
  • G. Davì et al.

    Platelet activation and atherothrombosis

    N. Engl. J. Med.

    (2007)
  • G. Davì et al.

    Oxidant stress, inflammation and atherogenesis

    Lupus

    (2005)
  • P. Ferroni et al.

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

    Curr. Med. Chem.

    (2007)
  • G.A. Limb et al.

    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.

    (1999)
  • A.M. Schmidt et al.

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

    J. Clin. Invest.

    (2001)
  • C.L. Verweij

    How RAGE turns in rage

    Genes Immun.

    (2002)
  • F. Santilli et al.

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

    Curr. Med. Chem.

    (2009)
  • N. Vazzana et al.

    Soluble forms of RAGE in internal medicine

    Intern. Emerg. Med.

    (2009)
  • Cited by (0)

    View full text