title: Estradiol augments while progesterone inhibits arginine transport in human endothelial cells through modulation of cationic amino acid transporter-1.
abstract: Decreased generation of nitric oxide (NO) by endothelial NO synthase (eNOS) characterizes endothelial dysfunction (ECD). Delivery of arginine to eNOS by cationic amino acid transporter-1 (CAT-1) was shown to modulate eNOS activity. We found in female rats, but not in males, that CAT-1 activity is preserved with age and in chronic renal failure, two experimental models of ECD. In contrast, during pregnancy CAT-1 is inhibited. We hypothesize that female sex hormones regulate arginine transport. Arginine uptake in human umbilical vein endothelial cells (HUVEC) was determined following incubation with either 17β-estradiol (E2) or progesterone. Exposure to E2 (50 and 100 nM) for 30 min resulted in a significant increase in arginine transport and reduction in phosphorylated CAT-1 (the inactive form) protein content. This was coupled with a decrease in phosphorylated MAPK/extracellular signal-regulated kinase (ERK) 1/2. Progesterone (1 and 100 pM for 30 min) attenuated arginine uptake and increased phosphorylated CAT-1, phosphorylated protein kinase Cα (PKCα), and phosphorylated ERK1/2 protein content. GO-6976 (PKCα inhibitor) prevented the progesterone-induced decrease in arginine transport. Coincubation with both progesterone and estrogen for 30 min resulted in attenuated arginine transport. While estradiol increases arginine transport and CAT-1 activity through modulation of constitutive signaling transduction pathways involving ERK, progesterone inhibits arginine transport and CAT-1 via both PKCα and ERK1/2 phosphorylation, an effect that predominates over estradiol.
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ohad S
authors.initials: OS
authors.lastname: Bentur
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Schwartz
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tamara
authors.initials: T
authors.lastname: Chernichovski
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Ingbir
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Weinstein
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Chernin
authors.affiliation: Department of Nephrology, Sackler School of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel idit.francesca@gmail.com.
authors.forename: Idit F
authors.initials: IF
authors.lastname: Schwartz
mesh_terms: D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport; D027201:Cationic Amino Acid Transporter 1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011374:Progesterone / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D027201:Cationic Amino Acid Transporter 1; D047428:Protein Kinase Inhibitors; C420825:SLC7A1 protein, human; D011374:Progesterone; D004958:Estradiol; D001120:Arginine; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: endothelial function; estrogen; progesterone