Catalytic consumption of nitric oxide by 12/15- lipoxygenase: inhibition of monocyte soluble guanylate cyclase activation.
12/15-Lipoxygenase (LOX) activity is elevated in vascular diseases associated with impaired nitric oxide (( small middle dot)NO) bioactivity, such as hypertension and atherosclerosis. In this study, primary porcine monocytes expressing 12/15-LOX, rat A10 smooth muscle cells transfected with murine 12/15-LOX, and purified porcine 12/15-LOX all consumed *NO in the presence of lipid substrate. Suppression of LOX diene conjugation by *NO was also found, although the lipid product profile was unchanged. *NO consumption by porcine monocytes was inhibited by the LOX inhibitor, eicosatetraynoic acid. Rates of arachidonate (AA)- or linoleate (LA)-dependent *NO depletion by porcine monocytes (2.68 +/- 0.03 nmol x min(-1) x 10(6) cells(-1) and 1.5 +/- 0.25 nmol x min(-1) x 10(6) cells(-1), respectively) were several-fold greater than rates of *NO generation by cytokine-activated macrophages (0.1-0.2 nmol x min(-1) x 10(6) cells(-1)) and LA-dependent *NO consumption by primary porcine monocytes inhibited *NO activation of soluble guanylate cyclase. These data indicate that catalytic *NO consumption by 12/15-LOX modulates monocyte *NO signaling and suggest that LOXs may contribute to vascular dysfunction not only by the bioactivity of their lipid products, but also by serving as catalytic sinks for *NO in the vasculature.
Coffey
M J
MJ
Wales Heart Research Institute, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom.
Natarajan
R
R
Chumley
P H
PH
Coles
B
B
Thimmalapura
P R
PR
Nowell
M
M
Kühn
H
H
Lewis
M J
MJ
Freeman
B A
BA
O'Donnell
V B
VB
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D002384:Catalysis; D018929:Cell Culture Techniques; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009130:Muscle, Smooth; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity; D013552:Swine; D014162:Transfection
D009569:Nitric Oxide; D001092:Arachidonate 12-Lipoxygenase; D006162:Guanylate Cyclase