Although L-arginine is the only substrate for nitric oxide (NO) production, no studies have yet been reported on the effect of an L-arginine deficiency on vascular function in humans. Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of dibasic amino acid transport caused by mutations in the SLC7A7 gene, resulting in an L-arginine deficiency. Vascular endothelial function was examined in an LPI patient who was shown to be a compound heterozygote for two mutations in the gene (5.3-kbp Alu-mediated deletion, IVS3+1G→Α). The lumen diameter of the brachial artery was measured in this patient and in healthy controls at rest, during reactive hyperemia (endothelium-dependent vasodilation [EDV]), and after sublingual nitroglycerin administration (endothelium-independent vasodilation [EIV]) using ultrasonography. Both EDV and NOx concentrations were markedly reduced in the patient compared with those for the controls. They became normal after an L-arginine infusion. EIV was not significantly different between the patient and controls. Positron emission tomography of the heart and a treadmill test revealed ischemic changes in the patient, which were improved by the L-arginine infusion. Thus, in the LPI patient, L-arginine deficiency caused vascular endothelial dysfunction via a decrease in NO production.
Yoshihiro Kamada, Hiroyuki Nagaretani, Shinji Tamura, Tohru Ohama, Takao Maruyama, Hisatoyo Hiraoka, Shizuya Yamashita, Akira Yamada, Shinichi Kiso, Yoshiaki Inui, Nobuyuki Ito, Yoshiro Kayanoki, Sumio Kawata, Yuji Matsuzawa
Submitter: Michael C. Reade, J. Duncan Young, C.A.R. Boyd | [email protected]
Dept. of Human Anatomy & Genetics and Nuffield Department of Anaesthetics, University of Oxford, UK
Published October 19, 2001
Kamada et al. recently published results demonstrating abnormal vascular reactivity in a patient with lysinuric protein intolerance (LPI) (1) which shed light on functional changes associated with absence of the y+LAT1 L-arginine transporter. We congratulate the authors on a thorough study, which demonstrates reduced systemic nitric oxide production and endothelium dependent vasodilation of the brachial artery of a patient with LPI, who also had a reduced plasma L-arginine concentration. Both these parameters were normalised by infusion of L-arginine to a supraphysiological concentration. However, we suggest the authors’ conclusion that the abnormal findings in this patient are due simply to a reduced plasma L-arginine concentration, and their implied assumption that absent y+LAT1 affects only intestinal L-arginine transport, may not be correct. In support of this, we have recently demonstrated that y+LAT1 mRNA is expressed in normal human arterial smooth muscle.
With ethical approval, human normal mesenteric arterial smooth muscle was obtained from 8 patients undergoing bowel resection for carcinoma. The quantity of mRNA encoding y+L transporter proteins (CD98, y+LAT1 and y+LAT2) was measured in a manner similar to that which we have previously described (2). All of these mRNAs were expressed at a high level in this tissue.
A genetic abnormality in y+LAT1 expression is thus very likely to affect more than just intestinal epithelial cells. The abnormal vascular function reported by Kamada et al. is likely to be at least in part due to abnormal L-arginine transport into the endothelial cells (and possibly the smooth muscle cells) of the vessels they studied. They report that supplemental L-arginine ‘normalised’ endothelium dependent vasodilation, but the plasma concentration of L-arginine used was in fact almost three times ‘normal’. We feel there is a strong possibility that this reflects a relative L-arginine insensitivity of the vessel in the absence of y+LAT1 function. If the only remaining L-arginine transporter was y+ (which has a Km of approximately 100uM compared to 10uM for y+L), one would predict that a supraphysiological plasma arginine concentration would return membrane arginine flux towards normal. Alternatively, it is possible that the vessel is able to compensate for the loss of y+LAT1 by upregulating expression of y+LAT2 or one of the CAT genes encoding the other membrane L -arginine transport system, y+.
Such considerations may help resolve some of the questions raised in the accompanying commentary by Loscalzo (3). We suggest that, in the absence of molecular studies of this patient’s vessels, experiments returning plasma arginine to its physiological value might help to clarify the nature of the vessel L-arginine transport abnormality.
References
1. Kamada, Y., Nagaretani, H., Tamura, S., Ohama, T., Maruyama, T., Hiraoka, H., Yamashita, S., Yamada, A., Kiso, S., Inui, Y., Ito, N., Kayanoki, Y., Kawata, S., Matsuzawa, Y. 2001. Vascular endothelial dysfunction resulting from L-arginine deficiency in a patient with lysinuric protein intolerance. J. Clin. Invest., 108, 717-724.
2. Reade, M.C., Young, J.D., Boyd, C.A.R. 2001. Cationic amino acid transporter mRNA levels in peripheral blood mononuclear cells from patients with septic shock. J. Physiol., 535P, S033.
3. Loscalzo, J. 2001. An experiment of nature: genetic L-arginine deficiency and NO insufficiency. J. Clin. Invest.,