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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/H2980    most recent 01173.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Duranski, M. R. Articles by Lefer, D. J. Search for Related Content PubMed PubMed Citation Articles by Duranski, M. R. Articles by Lefer, D. J.

Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury

¹Department of Medicine, Division of Cardiology, and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; and ²Department of Medicine, Boston University Medical Center, Whitaker Cardiovascular Institute, Boston, Massachusetts

Submitted 4 November 2005 ; accepted in final form 18 July 2006

Previous studies have shown that endothelial nitric oxide (NO) synthase (eNOS)-derived NO is an important signaling molecule in ischemia-reperfusion (I-R) injury. Deficiency of eNOS-derived NO has been shown to exacerbate injury in hepatic and myocardial models of I-R. We hypothesized that transgenic overexpression of eNOS (eNOS-TG) would reduce hepatic I-R injury. We subjected two strains of eNOS-TG mice to 45 min of hepatic ischemia and 5 h of reperfusion. Both strains were protected from hepatic I-R injury compared with wild-type littermates. Because the mechanism for this protection is still unclear, additional studies were performed by using inhibitors and activators of both soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) enzymes. Blocking sGC with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and HO-1 with zinc (III) deuteroporphyrin IX-2,4-bisethyleneglycol (ZnDPBG) in wild-type mice increased hepatic I-R injury, whereas pharmacologically activating these enzymes significantly attenuated I-R injury in wild-type mice. Interestingly, ODQ abolished the protective effects of eNOS overexpression, whereas ZnDPBG had no effect. These results suggest that hepatic protection in eNOS-TG mice may be mediated in part by NO signaling via the sGC-cGMP pathway and is independent of HO-1 signal transduction pathways.

nitric oxide; heme oxygenase-1; soluble guanyly cyclase; phosphodiesterase type 5 inhibition; endothelial nitric oxide synthase

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