title: Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury.
abstract: 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.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Duranski
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D003905:Deuteroporphyrins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D012720:Severity of Illness Index; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051547:Heme Oxygenase-1; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP