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1 Department of Medicine, Indiana University and Richard L. Roudebush Veterans Affairs Medical Centers, Indianapolis, Indiana 46202; and 2 Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224
Nitric oxide (·NO) attenuates hydrogen peroxide (H2O2)-mediated injury in porcine pulmonary artery endothelial cells (PAECs) and modulates intracellular levels of cGMP and cAMP. We hypothesized that ·NO attenuates H2O2-induced PAEC monolayer barrier dysfunction through cyclic nucleotide-dependent signaling mechanisms. To examine this hypothesis, cultured PAEC monolayers were treated with H2O2, and barrier function was measured as transmonolayer albumin clearance. H2O2 caused significant PAEC barrier dysfunction that was attenuated by intracellular as well as extracellular ·NO generation. ·NO increased PAEC cGMP and cAMP levels, but treatment with inhibitors of soluble guanylate cyclase or protein kinase G did not abrogate ·NO-mediated barrier protection. In contrast, H2O2 decreased protein kinase A activity, and inhibiting protein kinase A abrogated the protective effect of ·NO. H2O2-induced barrier dysfunction was not associated with decreased levels of cGMP or cAMP. 3-Isobutyl-1-methylxanthine and the cGMP analog 8-bromo-cGMP had little effect on H2O2-mediated endothelial barrier dysfunction, whereas 8-bromo-cAMP plus 3-isobutyl-1-methylxanthine was protective. These results indicate that ·NO modulates vascular endothelial barrier function through cAMP-dependent signaling mechanisms.
vascular endothelium; hydrogen peroxide; adenosine 3',5'-cyclic monophosphate; guanosine 3',5'-cyclic monophosphate; nitric oxide synthase
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