Augmented endothelial-specific L-arginine transport prevents obesity-induced hypertension.

Abstract

Hypertension is a major clinical complication of obesity. Our previous studies show that abnormal uptake of the nitric oxide precursor L-arginine, via the cationic amino acid transporter-1 (CAT1), contributes to endothelial dysfunction in cardiovascular disease. In this study, we tested the hypothesis that abnormal L-arginine transport may be a key mediator of obesity-induced hypertension. Mean arterial pressure (MAP) was monitored by telemetry in conscious wild-type (WT; n=13) mice, and transgenic mice with endothelial-specific overexpression of CAT1 (CAT+; n=14) fed a normal or a high fat diet for 20weeks. Renal angiotensin II (Ang II), CAT1 mRNA and plasma nitrate/nitrite levels were then quantified. In conjunction, plasma nitrate/nitrite levels were assessed in obese normotensive (n=15) and obese hypertensive subjects (n=15). Both genotypes of mice developed obesity when fed a high fat diet (P≤0.002). Fat fed WT mice had 13% greater MAP and 78% greater renal Ang II content, 42% lesser renal CAT1 mRNA levels and 42% lesser plasma nitrate/nitrite levels, than WT mice fed a normal fat diet (P≤0.02). In contrast, none of these variables were significantly altered by high fat feeding in CAT+ mice (P≥0.36). Plasma nitrate/nitrite levels were 17% less in obese hypertensives compared with obese normotensives (P=0.02). Collectively, these data indicate that obesity-induced down-regulation of CAT1 expression and subsequent reduced bioavailability of nitric oxide may contribute to the development of obesity-induced hypertension.