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


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.
Yang
Zhiyong
Z
Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, VIC 8008, Australia.
Venardos
Kylie
K
Jones
Emma
E
Morris
Brian J
BJ
Chin-Dusting
Jaye
J
Kaye
David M
DM
D024509:3' Flanking Region / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001120:Arginine / Q000378:metabolism; D016466:CHO Cells; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000378:metabolism*; D005787:Gene Frequency; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D051379:Mice; D009569:Nitric Oxide; D009924:Organ Culture Techniques; D011110:Polymorphism, Genetic; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
D027201:Cationic Amino Acid Transporter 1; C420825:SLC7A1 protein, human; D014665:Vasodilator Agents; D009569:Nitric Oxide; D001120:Arginine