期刊
ACTA PHYSIOLOGICA
卷 210, 期 4, 页码 845-853出版社
WILEY
DOI: 10.1111/apha.12215
关键词
cationic amino acid transporter-1; hypertension; l-arginine transport; nitric oxide; oxidative stress
类别
资金
- National Health and Medical Research Council, Australia [384299, 1036352]
- National Heart Foundation, Australia [PF09M4668, PF09M4698]
- Victorian Government's Operational Infrastructure Support Program
AimOxidative 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. MethodsWild-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; 30mgkg(-1)day(-1); 14days) 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 F-2-isoprostane levels. ResultsBasal MAP was less in CAT+ (922mmHg; n=6) than in WT (98 +/- 2mmHg; 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 (P-DETCA*genotype=0.006). DETCA infusion increased total plasma F-2-isoprostane levels (by 67 +/- 11%; P=0.05) in WT but not in CAT+. Total renal F-2-isoprostane levels were greater during DETCA infusion in WT (by 72%; P<0.001), but not in CAT+, compared to appropriate controls. ConclusionAugmented 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.
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