Journal of Molecular Medicine

, Volume 88, Issue 1, pp 75–83 | Cite as

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

  • Markus van der Giet
  • Markus Tölle
  • Domenico Pratico
  • Volkmar Lufft
  • Mirjam Schuchardt
  • Matthias P. Hörl
  • Walter Zidek
  • Uwe J. F. Tietge
Original Article
First Online:
Received:
Revised:
Accepted:

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.

Keywords

sPLA2 Oxidative stress End-stage renal disease Endothelial dysfunction 
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Notes

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.)

Disclosures

None.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Markus van der Giet
    • 1
  • Markus Tölle
    • 1
  • Domenico Pratico
    • 2
  • Volkmar Lufft
    • 3
  • Mirjam Schuchardt
    • 1
  • Matthias P. Hörl
    • 1
  • Walter Zidek
    • 1
  • Uwe J. F. Tietge
    • 1
    • 4
  1. 1.Medizinische Klinik IV—NephrologyCharite—Campus Benjamin FranklinBerlinGermany
  2. 2.Department of Pharmacology, School of MedicineTemple UniversityPhiladelphiaUSA
  3. 3.Nephrologisches Zentrum Rendsburg-EckernfördeRendsburgGermany
  4. 4.Center for Liver, Digestive and Metabolic Diseases, Department of PediatricsUniversity Medical Center GroningenGroningenThe Netherlands

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