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Increased type IIA secretory phospholipase A2 expression contributes to oxidative stress in end-stage renal disease

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Abstract

End-stage renal disease (ESRD) patients exhibit increased in vivo oxidative stress conceivably contributing to cardiovascular mortality. The type IIA secretory phospholipase A2 (sPLA2) has proatherogenic activity. We explored the hypothesis that sPLA2 contributes to oxidative stress generation and endothelial dysfunction in ESRD patients and transgenic (tg) mice. Patients with ESRD had increased in vivo oxidative stress as assessed by plasma isoprostane levels (p < 0.001). Active sPLA2 in plasma was substantially increased compared with healthy controls (1,156 ± 65 versus 184 ± 5 ng/dL, p < 0.001) and correlated with plasma isoprostanes (r = 0.61, p < 0.001). Correspondingly, human sPLA2 tg mice display increased generation of reactive oxygen species within aortic vascular smooth muscle cells, leading to severe endothelial dysfunction (maximal vasodilation in response to 10 µmol/L acetylcholine, sPLA2 36 ± 8%, controls 80 ± 2% of phenylephrine-induced vasoconstriction). Increased vascular oxidative stress in sPLA2 tg mice is dependent on the induction of vascular cyclooxygenase (COX)2 expression. Conversely, ESRD patients show increased formation of COX2-derived prostaglandins (p < 0.05) correlated with plasma sPLA2 (r = 0.71, p < 0.05). Our data indicate that increased expression of sPLA2 might represent a novel causative risk factor contributing to the increased cardiovascular disease morbidity and mortality in ESRD.

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Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft (Ti 268/2-1 to U.J.F.T.), the Netherlands Organization for Scientific Research (VIDI Grant 917-56-358; to U.J.F.T.), the Sonnenfeld-Stiftung (M.v.d.G), and the Else Kröner-Fresenius-Stiftung (to M.v.d.G. and U.J.F.T.)

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Authors and Affiliations

  1. Medizinische Klinik IV—Nephrology, Charite—Campus Benjamin Franklin, Berlin, Germany

    Markus van der Giet, Markus Tölle, Mirjam Schuchardt, Matthias P. Hörl, Walter Zidek & Uwe J. F. Tietge

  2. Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA, USA

    Domenico Pratico

  3. Nephrologisches Zentrum Rendsburg-Eckernförde, Rendsburg, Germany

    Volkmar Lufft

  4. Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    Uwe J. F. Tietge

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  1. Markus van der Giet
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Correspondence to Uwe J. F. Tietge.

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van der Giet and Tölle equally contributed to this manuscript.

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van der Giet, M., Tölle, M., Pratico, D. et al. Increased type IIA secretory phospholipase A2 expression contributes to oxidative stress in end-stage renal disease. J Mol Med 88, 75–83 (2010). https://doi.org/10.1007/s00109-009-0543-3

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  • DOI: https://doi.org/10.1007/s00109-009-0543-3

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