Increased cationic amino acid flux through a newly expressed transporter in cells overproducing nitric oxide from patients with septic shock.
Increased production of nitric oxide (NO) is thought to be a factor in the pathogenesis of many human diseases - among them the hypotension that often accompanies sepsis. The supply of the cationic amino acid arginine is known to be rate-limiting for NO production. We hypothesized that cationic amino acid transport might be increased in cells producing excess NO from patients with septic shock. Peripheral blood mononuclear cells were isolated from patients with sepsis and from healthy control subjects. The rates of both NO production and cationic amino acid uptake were increased in cells from patients with septic shock. The increased transport was due almost entirely to an increase in the activity of one transporter, subtype y+. The activity of the other major cationic amino acid transporter (y+L) was unchanged. The expression of CAT2 mRNA, which encodes a y+ transporter protein, was also increased in these cells. We suggest that CAT2 might be a therapeutic target to prevent excess NO production in sepsis and possibly other human disease states, while leaving basal production unchanged.
Reade
Michael C
MC
Nuffield Department of Anaesthetics, University of Oxford, Radcliffe Infirmary, UK. michael.reade@brasenose.oxford.ac.uk
Clark
Megan F
MF
Young
J Duncan
JD
Boyd
C A R
CA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D027182:Amino Acid Transport System y+ / Q000097:blood; D027241:Amino Acid Transport System y+L / Q000097:blood; D026923:Amino Acid Transport Systems, Basic / Q000097:blood*; D001120:Arginine / Q000097:blood; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic / Q000097:blood*
D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D026923:Amino Acid Transport Systems, Basic; D012333:RNA, Messenger; D009569:Nitric Oxide; D001120:Arginine