Tetrahydrobiopterin synthesis is induced by LPS in vascular smooth muscle and is rate-limiting for nitric oxide production.
GTPCH1 mRNA and BH4 synthesis is increased by LPS in vascular smooth muscle. Our data suggest that induction of GTPCH1 and NOS represent two arms of a common pathway required for immunostimulant-evoked NO synthesis. This conclusion is consistent with the view that the major function of immunostimulant-evoked BH4 is to support NOS. Moreover, GTPCH1 and other enzymes of the de novo BH4 synthetic pathway may prove to be important targets for therapy of clinical conditions arising from NO overproduction. As we begin to reveal the molecular events governing the induction and expression of GTPCH1 and NOS, additional therapeutic approaches for treating NO overproduction are certain to be revealed.
Gross
S S
SS
Department of Pharmacology, Cornell University Medical College, New York, NY 10021.
Levi
R
R
Madera
A
A
Park
K H
KH
Vane
J
J
Hattori
Y
Y
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004790:Enzyme Induction; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
D008070:Lipopolysaccharides; D011621:Pteridines; D011622:Pterins; D012333:RNA, Messenger; D001708:Biopterins; D009569:Nitric Oxide; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006136:GTP Cyclohydrolase; C003402:sapropterin