Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1: contribution to hypertension and endothelial dysfunction.

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Yang Z, Venardos K, Jones E, Morris BJ, Chin-Dusting J, Kaye DM

Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1: contribution to hypertension and endothelial dysfunction.

Circulation. 2007 Mar 13;115(10):1269-74. Epub 2007 Feb 26.

PubMed ID

17325243 [ View in PubMed

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Abstract

BACKGROUND: Endothelial dysfunction because of reduced nitric oxide bioavailability is a key feature of essential hypertension. We have found that normotensive siblings of subjects with essential hypertension have impaired endothelial function accompanied by altered arginine metabolism. METHODS AND RESULTS: We have identified a novel C/T polymorphism in the 3'UTR of the principal arginine transporter, solute carrier family 7 (cationic amino acid transporter, y+ system), member 1 gene (SLC7A1). The minor T allele significantly attenuates reporter gene expression (P<0.01) and is impaired in its capacity to form DNA-protein complexes (P<0.05). In 278 hypertensive subjects the frequency of the T allele was 13.3% compared with 7.6% in 498 normotensive subjects (P<0.001). Moreover, the overall genotype distribution observed in hypertensives differed significantly from that in normotensives (P<0.001). To complement these studies, we generated an endothelial-specific transgenic mouse overexpressing L-arginine transporter SLC7A1. The Slc7A1 transgenic mice exhibited significantly enhanced responses to the endothelium-dependent vasodilator acetylcholine (-log EC50 for wild-type versus Slc7A1 transgenic: 6.87+/-0.10 versus 7.56+/-0.13; P<0.001). This was accompanied by elevated production of nitric oxide by isolated aortic endothelial cells. CONCLUSIONS: The present study identifies a key, functionally active polymorphism in the 3'UTR of SLC7A1. As such, this polymorphism may account for the apparent link between altered endothelial function, L-arginine, and nitric oxide metabolism and predisposition to essential hypertension.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Arginine	High affinity cationic amino acid transporter 1	Protein	Humans	Unknown	Not Available	Details