Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1)
2012
Abstract Elevated plasma concentrations of endogenously formed asymmetric (ADMA) and symmetric dimethyl -l ‐arginine (SDMA) are associated with adverse clinical outcomes. Our aim was to investigate the cellular uptake properties of ADMA by the human cationic amino acid transporter 1 (CAT1; SLC7A1 ). Human embryonic kidney cells (HEK293) stably overexpressing CAT1 (HEK-CAT1) and vector-transfected control cells (HEK-VC) were established to determine cellular uptake of labeled [ 3 H]ADMA and [ 3 H] l -arginine. Uptake of ADMA and l -arginine were significantly ( p V max values of cellular ADMA and l -arginine uptake by CAT1 were 26.9 ± 0.8 and 11.0 ± 0.2 nmol mg protein − 1 min − 1 , respectively. K m values were 183 ± 21 μmol l − 1 (ADMA) and 519 ± 36 μmol l − 1 ( l- arginine). Uptake of ADMA was inhibited by l -arginine and SDMA with IC 50 values (95% CI) of 227 (69–742) μmol l − 1 and 273 (191–390) μmol l − 1 , respectively. ADMA and SDMA inhibited CAT1-mediated uptake of l -arginine with IC 50 values of 758 (460–1251) μmol l − 1 and 789 (481–1295) μmol l − 1 , respectively. Efflux of ADMA was significantly increased in HEK-CAT1 cells as compared to HEK-VC ( p CAT1 mediates the cellular uptake of ADMA. In its physiological concentration range ADMA is unlikely to impair CAT1-mediated transport of l -arginine. Conversely, high (but still physiological) concentrations of l -arginine can inhibit CAT1-mediated cellular uptake of ADMA.
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