Brain Advance Access originally published online on April 7, 2005
Brain 2005 128(7):1613-1621; doi:10.1093/brain/awh492
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Lack of oestrogen protection in amyloid-mediated endothelial damage due to protein nitrotyrosination
1 Laboratori de Fisiologia Molecular, Unitat de Senyalització Cellular and 2 Unitat de Proteòmica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
Correspondence to: Dr Francisco J. Muñoz, Laboratori de Fisiologia Molecular, Unitat de Senyalització Cellular, Universitat Pompeu Fabra, Carrer Dr Aiguader 80, Barcelona 08003, Spain E-mail: paco.munoz{at}upf.edu
Amyloid ß-peptide (Aß) cytotoxicity, the hallmark of Alzheimer's disease, implicates oxidative stress in both neurons and vascular cells, particularly endothelial cells. Consequently, antioxidants have shown neuroprotective activities against Aß-induced cytotoxicity. Among the different antioxidants used in both in vitro and in vivo studies, 17ß-oestradiol (E2) has garnered the most attention. Oestrogen attenuated AßE22Q-induced toxicity in neurons but failed to protect endothelial cells. Here we show that E2-mediated activation of endothelial nitric oxide synthase (eNOS) increases the production of nitric oxide (NO), which, under AßE22Q-induced oxidative damage, results in the formation of peroxynitrite and increased nitration of tyrosine residues. Inhibition of eNOS prevents nitrotyrosination and permits E2-mediated protection against AßE22Q on endothelial cells. The main nitrotyrosinated proteins in the presence of E2 and AßE22Q were identified by MALDI-TOF mass spectrometry. These proteins are key players in the regulation of energy production, cytoskeletal integrity, protein metabolism and protection against oxidative stress. Our data highlight the potential damaging consequences of E2 in vascular disorders dealing with oxidative stress conditions, such as cerebral amyloid angiopathy, stroke and ischaemia-reperfusion conditions.
Key Words: Alzheimer's disease; amyloid ß-peptide; oestrogen; nitric oxide; nitrotyrosination
Abbreviations: Aß = amyloid ß-peptide; E2 = 17ß-oestradiol; ECs = endothelial cells; eNOS = endothelial nitric oxide synthase; HA-VSMCs = human aortic vascular smooth muscle cells; HUVECs = human umbilical vein endothelial cells; L-NNA = NG-nitro-L-arginine; NO = nitric oxide; NOS = NO synthase; PTIO = 4,5,5-tetramethylimidazoline-1-oxyl 3-oxide
Received November 11, 2004. Revised February 14, 2005. Accepted March 1, 2005.
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