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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1976.)
© 2007 American Heart Association, Inc.

Vascular Biology

Differential Regulation of Homocysteine Transport in Vascular Endothelial and Smooth Muscle Cells

Xiaohua Jiang; Fan Yang; Eugen Brailoiu; Hieronim Jakubowski; Nae J. Dun; Andrew I. Schafer; Xiaofeng Yang; William Durante; Hong Wang

From the Department of Pharmacology (X.J., F.Y., E.B., N.J.D., X.Y., H.W.), Temple University School of Medicine, Philadelphia, Pa; the Department of Microbiology & Molecular Genetics (H.J.), UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ; the Institute of Bioorganic Chemistry (H.J.), Polish Academy of Sciences, 61704 Poznan, Poland; the Department of Medicine (A.I.S.), Weill Cornell Medical College, New York, NY; the Department of Medicine (X.Y., H.W.), University of Pennsylvania School of Medicine, Philadelphia, PA; the Department of Medicine (X.Y., H.W.), Baylor College of Medicine, Houston, TX; and the Department of Medical Pharmacology and Physiology (W.D.), University of Missouri School of Medicine, Columbia, MI.

Correspondence to Hong Wang, Temple University School of Medicine, Department of Pharmacology, 3420 North Broad Street, Philadelphia, PA 19140. E-mail hongw{at}temple.edu

Objective— We previously reported that homocysteine (Hcy) inhibits endothelial cell (EC) growth and promotes vascular smooth muscle cell (VSMC) proliferation. This study characterized and directly compared Hcy transport in cultured human aortic ECs (HAECs) and smooth muscle cells (HASMCs).

Methods and Results— Hcy (10 µmol/L) was transported into both cell types in a time-dependent fashion but was approximately 4-fold greater in HASMCs, and is nonstereoenantiomer specific. Hcy transport in HAECs had a Michaelis-Menten constant (Km) of 39 µmol/L and a maximal transport velocity (Vmax) of 873 pmol/mg protein/min. In contrast, Hcy transport in HASMCs had a lower affinity (Km=106 µmol/L) but a higher transport capacity (Vmax=4192 pmol/mg protein/min). Competition studies revealed that the small neutral amino acids tyrosine, cysteine, glycine, serine, alanine, methionine, and leucine inhibited Hcy uptake in both cell types, but the inhibition was greater for tyrosine, serine, glycine, and alanine in HAECs. Sodium-depletion reduced Hcy transport to 16% in HAECs and 56% in HASMCs. Increases in pH from 6.5 to 8.2 or lysosomal inhibitors blocked Hcy uptake only in HAECs. In addition, Hcy shares carrier systems with cysteine, in a preferable order of alanine-serine-cysteine (ASC)>aspartate and glutamate (X_AG)=large branched-chain neutral amino acids (L) transporter systems in HAECs and ASC>L>X_AG in HASMCs. The sodium-dependent system ASC plays a predominant role for Hcy transport in vascular cells.

Conclusions— Transport system ASC predominantly mediates Hcy transport in EC and is lysosomal dependent.

Homocysteine transport is differentially regulated in vascular cells. In endothelial cells, Hcy transport has higher affinity, lower transport capacity, and predominantly mediated by a sodium/lysosome-dependent system ASC. Hcy shares carrier systems with cysteine, in a preferable order of ASC > X_AG=L transporter systems in HAECs and ASC>L>X_AG in HASMCs.

Key Words: Homocysteine transport • vascular cells

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