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

Yang, Zhiyong, Venardos, Kylie, Jones, Emma, Morris, Brian J., Chin-Dusting, Jaye and Kaye, David M. 2007, Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1 : contribution to hypertension and endothelial dysfunction, Circulation, vol. 115, no. 10, pp. 1269-1274.

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Title Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1 : contribution to hypertension and endothelial dysfunction
Author(s) Yang, Zhiyong
Venardos, Kylie
Jones, Emma
Morris, Brian J.
Chin-Dusting, Jaye
Kaye, David M.
Journal name Circulation
Volume number 115
Issue number 10
Start page 1269
End page 1274
Total pages 6
Publisher Lippincott Williams and Wilkins
Place of publication Baltimore, Md.
Publication date 2007-03
ISSN 0009-7322
1524-4539
Keyword(s) amino acids
endothelium
genes
genetics
hypertension
molecular biology
nitric oxide
Summary 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.
Language eng
Field of Research 069999 Biological Sciences not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2007, American Heart Association, Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30048042

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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