Evidence for increased methylglyoxal in the vasculature of women with preeclampsia: role in upregulation of LOX-1 and arginase.
Preeclampsia is characterized by vascular endothelial dysfunction partly attributed to oxidative stress. In the vasculature of preeclamptic women, we have shown increased lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and arginase expression, which can contribute to vascular oxidative stress. However, the mechanisms of such upregulation are unknown. Methylglyoxal (MG) that plays a role in the vascular complications of diabetes mellitus and the development of hypertension can be one potential factor that can affect LOX-1 and arginase through its ability to induce oxidative stress in vascular cells. MG also reacts with lysine residues in proteins to generate advanced glycation end product, N(epsilon)-carboxy ethyl lysine, which also serves as a marker of MG. We hypothesized that markers of MG formation will be increased in the vasculature of preeclamptic women and that exogenous MG will induce oxidative stress by the upregulation of LOX-1 via arginase. We observed increased N(epsilon)-carboxy ethyl lysine expression in the vasculature of women with preeclampsia in comparison with normotensive pregnant women. Moreover, glyoxalase I and II, enzymes that detoxify MG, and glutathione reductase, which generates reduced glutathione, a cofactor for glyoxalase, are also reduced in preeclampsia. In cultured endothelial cells, MG increased arginase expression by 6 hours and LOX-1 expression by 24 hours. Inhibition of arginase or NO synthase significantly reduced MG-induced LOX-1 expression, superoxide levels, and nitrotyrosine staining. In conclusion, MG-induced LOX-1 expression is mediated via arginase upregulation likely because of uncoupling of NO synthase, which may have implications in preeclampsia.
Sankaralingam
Sowndramalingam
S
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Xu
Han
H
Jiang
Yanyan
Y
Sawamura
Tatsuya
T
Davidge
Sandra T
ST
D000328:Adult; D001119:Arginase / Q000378:metabolism*; D001158:Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000378:metabolism; D000099301:Hydroxyacylglutathione Hydrolase
D001119:Arginase; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D007791:Lactoylglutathione Lyase; D008239:Lysine; D019001:Nitric Oxide Synthase; D030421:Peroxynitrous Acid; D011765:Pyruvaldehyde; D051127:Scavenger Receptors, Class E; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase; C495137:OLR1 protein, human; C048496:N(6)-carboxymethyllysine