End-stage renal disease (ESRD) patients exhibit increased in vivo oxidative stress conceivably contributing to cardiovascular mortality. The type IIA secretory phospholipase A(2) (sPLA(2)) has proatherogenic activity. We explored the hypothesis that sPLA(2) 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 sPLA(2) 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 sPLA(2) 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 micromol/L acetylcholine, sPLA(2) 36 +/- 8%, controls 80 +/- 2% of phenylephrine-induced vasoconstriction). Increased vascular oxidative stress in sPLA(2) 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 sPLA(2) (r = 0.71, p < 0.05). Our data indicate that increased expression of sPLA(2) might represent a novel causative risk factor contributing to the increased cardiovascular disease morbidity and mortality in ESRD.