Arginase-1 overexpression induces cationic amino acid transporter-1 in psoriasis.
Regulated uptake of extracellular l-arginine by cationic amino acid transporters (CATs) is required for inducible nitric oxide synthase and arginase activity. Both enzymes were recently recognized as important in the pathophysiology of psoriasis because of their contribution to epidermal hyperproliferation. We here characterize the expression pattern of CATs in psoriatic skin compared to healthy skin. CAT-1 mRNA expression was strongly upregulated in lesional and nonlesional areas of psoriatic skin compared to healthy skin, whereas expression of CAT-2A and the inducible isoform CAT-2B was unaltered in psoriatic skin. Furthermore, we tested the hypothesis that arginase-1 overexpression regulates CAT expression via intracellular l-arginine concentration. In in vitro experiments with arginase-1 overexpressing HaCaT cells, CAT-1 mRNA expression was increased. Likewise, this occurs in l-arginine-starved HaCaT cells. Both CAT-2 isoforms were not affected. Arginase-1 overexpression limits the synthesis of NO at physiological, but not supraphysiological, l-arginine levels. Plasma l-arginine concentration was diminished in psoriasis patients and the arginase product l-ornithine was significantly increased compared to healthy controls. In summary, arginase-1 overexpression leads to upregulated CAT-1 expression in psoriatic skin, which is due to lowered intracellular l-arginine levels and limits NO synthesis at physiological l-arginine concentrations.
Schnorr
Oliver
O
Institute for Biochemistry and Molecular Biology I, Building 22.03, Heinrich-Heine-University Duesseldorf, Universitaetsstr.1, D-40225 Duesseldorf, Germany. schnorr@uni-duesseldorf.de
Schuier
Maximilian
M
Kagemann
Guido
G
Wolf
Ronald
R
Walz
Markus
M
Ruzicka
Thomas
T
Mayatepek
Ertan
E
Laryea
Maurice
M
Suschek
Christoph V
CV
Kolb-Bachofen
Victoria
V
Sies
Helmut
H
D001119:Arginase / Q000378:metabolism*; D001483:Base Sequence; D027201:Cationic Amino Acid Transporter 1 / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011565:Psoriasis / Q000201:enzymology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D027201:Cationic Amino Acid Transporter 1; D017931:DNA Primers; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D001119:Arginase