Cardiovascular Research Advance Access first published online on August 14, 2009
This version [Corrected Proof] published online on September 3, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp277
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Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia
1 Department of Physiology, University of Alberta, Edmonton, Canada
2 Department of Obstetrics and Gynaecology, Women and Children's Health Research Institute, Cardiovascular Research Centre and Mazankowski Alberta Heart Institute, 232 HMRC, University of Alberta, Edmonton, Canada T6G 2S2
* Corresponding author. Tel: +1 780 492 1864, Fax: +1 780 492 1308, Email: sandra.davidge{at}ualberta.ca
Aims: Preeclampsia is a hypertensive disorder characterized by vascular oxidative stress. Decreased availability of the vasodilator nitric oxide (NO) has been postulated to be involved in the pathophysiology of this disorder. Arginase, an enzyme that competes with nitric oxide synthase (NOS) for L-arginine, not only reduces NO formation but also increases superoxide production by NOS. In placenta of preeclamptic women, arginase upregulation has been shown to be increased and contributes to superoxide formation via uncoupling of NOS. However, the role of arginase in the maternal vasculature is not clear. We hypothesized that arginase would be upregulated in the maternal vasculature of women with preeclampsia and contribute to oxidative stress within the endothelium.
Methods and results: We observed increased arginase expression in the maternal vasculature of women with preeclampsia compared with normotensive pregnant women. Furthermore, human umbilical vein endothelial cells treated with 2% plasma from preeclamptic women show increased arginase II expression and activity that was reduced by a peroxynitrite scavenger. Also, both 3-morpholino sydnonimine and exogenous peroxynitrite increased arginase expression and activity. Preeclamptic plasma treatment increased superoxide and peroxynitrite levels. Superoxide levels were significantly reduced after arginase and NOS inhibition with [(S)-(2-boronoethyl)-L-cysteine] and N
-nitro-L-arginine methyl ester, respectively, but peroxynitrite levels were in fact increased after arginase inhibition. Moreover, in the presence of preeclamptic plasma, L-arginine supplementation increased peroxynitrite formation during arginase inhibition.
Conclusion: Increased arginase expression in preeclampsia can induce uncoupling of NOS as a source of superoxide in the maternal vasculature in preeclampsia. However, L-arginine supplementation in the face of oxidative stress could lead to a further increase in peroxynitrite.
KEYWORDS Pregnancy; Preeclampsia; Endothelium; Arginase; Peroxynitrite; Nitric oxide; Superoxide
Time for primary review: 44 days