This Article Full Text Full Text (PDF) All Versions of this Article: 115/10/1269    most recent CIRCULATIONAHA.106.665836v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yang, Z. Articles by Kaye, D. M. Search for Related Content PubMed PubMed Citation Articles by Yang, Z. Articles by Kaye, D. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE NITRIC OXIDE Medline Plus Health Information High Blood Pressure Related Collections Other hypertension Endothelium/vascular type/nitric oxide

(Circulation. 2007;115:1269-1274.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Identification of a Novel Polymorphism in the 3'UTR of the L-Arginine Transporter Gene SLC7A1

Contribution to Hypertension and Endothelial Dysfunction

Zhiyong Yang, PhD; Kylie Venardos, PhD; Emma Jones, BSc; Brian J. Morris, PhD; Jaye Chin-Dusting, PhD; David M. Kaye, MD, PhD

From the Wynn Department of Metabolic Cardiology (Z.Y., K.V., D.M.K.) and Vascular Pharmacology Laboratory (E.J., J.C.-D.), Baker Heart Research Institute, Melbourne; and School of Medical Sciences and Bosch Institute (B.J.M.), University of Sydney, Sydney, Australia.

Correspondence to Dr David M. Kaye, Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, VIC 8008, Australia. E-mail david.kaye{at}baker.edu.au

Received September 19, 2006; accepted December 18, 2006.

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.

---

 

CLINICAL PERSPECTIVE