title: Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells.
abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. ADMA accumulation, mainly due to a decreased dimethylarginine dimethylaminohydrolase (DDAH) activity, has been related to the development of cardiovascular diseases. We investigate whether estradiol prevents the changes induced by oxidized low density lipoprotein (oxLDL) on the DDAH/ADMA/NO pathway in human umbilical artery endothelial cells (HUAEC). HUAEC were exposed to estradiol, native LDL (nLDL), oxLDL and their combinations for 24 h. In some experiments, cells were also exposed to the unspecific estrogen receptor (ER) antagonist ICI 182780, the specific ERα antagonist MPP or specific agonists for ERα, ERβ and GPER. ADMA concentration was measured by HPLC and concentration of NO by amperometry. Protein expression and DDAH activity were measured by immunoblotting and an enzymatic method, respectively. oxLDL, but not nLDL, increased ADMA concentration with a concomitant decrease on DDAH activity. oxLDL reduced eNOS protein and NO production. Estradiol alone had no effects on DDAH/ADMA/NO pathway, but increased the attenuated endothelial NO production induced by oxLDL by reduction in ADMA and preventing loss of eNOS protein levels. ICI 182780 and MPP completely abolished these effects of estradiol on oxLDL-exposed cells. ERα agonist, but not ERβ and GPER agonists, mirrored estradiol effects on NO production. In conclusion, estradiol restores (1) DDAH activity, and therefore ADMA levels, and (2) NO production impaired by oxLDL in HUAEC acting through ERα.
authors.affiliation: Research Foundation, Hospital Clínico of Valencia - INCLIVA, Valencia, Spain. susana.novella@uv.es
authors.forename: Susana
authors.initials: S
authors.lastname: Novella
authors.forename: Andrés
authors.initials: A
authors.lastname: Laguna-Fernández
authors.forename: Macarena
authors.initials: M
authors.lastname: Lázaro-Franco
authors.forename: Agua
authors.initials: A
authors.lastname: Sobrino
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueno-Betí
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Tarín
authors.forename: Elena
authors.initials: E
authors.lastname: Monsalve
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchís
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001120:Arginine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014469:Umbilical Arteries / Q000166:cytology
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; C109584:GPER1 protein, human; D007527:Isoenzymes; D008077:Lipoproteins, LDL; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D004958:Estradiol; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D000581:Amidohydrolases; C059999:dimethylargininase