title: Endothelial cationic amino acid transporter-1 overexpression can prevent oxidative stress and increases in arterial pressure in response to superoxide dismutase inhibition in mice.
abstract: OBJECTIVE
  Oxidative stress may play an important role in the pathogenesis of hypertension. The aim of our study is to examine whether increased expression of the predominant endothelial l-arginine transporter, cationic amino acid transporter-1 (CAT1), can prevent oxidative stress-induced hypertension.
  
  
  METHODS
  Wild-type mice (WT; n = 9) and endothelial CAT1 overexpressing (CAT+) mice (n = 6) had telemetry probes implanted for the measurement of mean arterial pressure (MAP), heart rate (HR) and locomotor activity. Minipumps were implanted for infusion of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg kg(-1) day(-1) ; 14 days) or its saline vehicle. Baseline levels of MAP, HR and locomotor activity were determined before and during chronic DETCA administration. Mice were then killed, and their plasma and kidneys collected for analysis of F2 -isoprostane levels.
  
  
  RESULTS
  Basal MAP was less in CAT+ (92 ± 2 mmHg; n = 6) than in WT (98 ± 2 mmHg; n = 9; P < 0.001). During DETCA infusion, MAP was increased in WT (by 4.2 ± 0.5%; P < 0.001) but not in CAT+, when compared to appropriate controls (PDETCA*genotype = 0.006). DETCA infusion increased total plasma F2 -isoprostane levels (by 67 ± 11%; P = 0.05) in WT but not in CAT+. Total renal F2 -isoprostane levels were greater during DETCA infusion in WT (by 72%; P < 0.001), but not in CAT+, compared to appropriate controls.
  
  
  CONCLUSIONS
  Augmented endothelial l-arginine transport attenuated the prohypertensive effects of systemic and renal oxidative stress, suggesting that manipulation of endothelial CAT1 may provide a new therapeutic approach for the treatment of cardiovascular disease associated with oxidative stress.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia; Department of Physiology, Monash University, Melbourne, Vic., Australia.
authors.forename: G
authors.initials: G
authors.lastname: Konstantinidis
authors.forename: G A
authors.initials: GA
authors.lastname: Head
authors.forename: R G
authors.initials: RG
authors.lastname: Evans
authors.forename: T-P
authors.initials: TP
authors.lastname: Nguyen-Huu
authors.forename: K
authors.initials: K
authors.lastname: Venardos
authors.forename: K D
authors.initials: KD
authors.lastname: Croft
authors.forename: T A
authors.initials: TA
authors.lastname: Mori
authors.forename: D M
authors.initials: DM
authors.lastname: Kaye
authors.forename: N W
authors.initials: NW
authors.lastname: Rajapakse
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D028421:Isoprostanes; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D028421:Isoprostanes; D050916:TRPV Cation Channels; C446923:Trpv6 protein, mouse; D004958:Estradiol; C073106:3,17-diacetoxyestra-1,3,5(10)-trien-2-carboxylic acid; D013482:Superoxide Dismutase
keywords: cationic amino acid transporter-1; hypertension; l-arginine transport; nitric oxide; oxidative stress