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Departments of 1 Pharmacology, 2 Physiology, and 3 Medicine, New York Medical College, Valhalla, New York 10595
Carbon monoxide (CO) stimulates guanylate
cyclase (GC) and increases guanosine 3',5'-cyclic monophosphate (cGMP)
levels. We transfected rat-lung pulmonary endothelial cells with a
retrovirus-mediated human heme oxygenase (hHO)-1 gene. Pulmonary cells
that expressed hHO-1 exhibited a fourfold increase in HO activity
associated with decreases in the steady-state levels of heme and cGMP
without changes in soluble GC (sGC) and endothelial nitric oxide
synthase (NOS) proteins or basal nitrite production. Heme elicited
significant increases in CO production and intracellular cGMP levels in
both pulmonary endothelial and pulmonary hHO-1-expressing cells.
N
-nitro-L-arginine methyl ester
(L-NAME), an inhibitor of NOS, significantly decreased cGMP
levels in heme-treated pulmonary endothelial cells but not heme-treated
hHO-1-expressing cells. In the presence of exogenous heme, CO and cGMP
levels in hHO-1-expressing cells exceeded the corresponding levels in
pulmonary endothelial cells. Acute exposure of endothelial cells to
SnCl2, which is an inducer of HO-1, increased cGMP levels,
whereas chronic exposure decreased heme and cGMP levels. These results
indicate that prolonged overexpression of HO-1 ultimately decreases sGC
activity by limiting the availability of cellular heme. Heme activates
sGC and enhances cGMP levels via a mechanism that is largely
insensitive to NOS inhibition.
guanosine 3',5'-cyclic monophosphate; retroviral vector; soluble guanylate cyclase; heme oxygenase
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