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Published on: August 7, 2012
Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
Mark R Duranski1, John W Elrod, John W Calvert
1Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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.
Insights
Transgenic overexpression of endothelial nitric oxide synthase (eNOS) protected against liver ischemia-reperfusion (I-R) injury. This protection was mediated by the soluble guanylyl cyclase (sGC) pathway, not heme oxygenase-1 (HO-1).
Area of Science:
- Cardiovascular Biology
- Hepatology
- Molecular Medicine
Background:
- Endothelial nitric oxide (NO) synthase (eNOS)-derived NO is crucial in signaling during ischemia-reperfusion (I-R) injury.
- eNOS-derived NO deficiency exacerbates hepatic and myocardial I-R injury.
- Transgenic overexpression of eNOS (eNOS-TG) may offer protection against hepatic I-R injury.
Purpose of the Study:
- To investigate the protective effects of eNOS overexpression in a mouse model of hepatic I-R injury.
- To elucidate the signaling pathways involved in eNOS-mediated protection against hepatic I-R injury.
Main Methods:
- Hepatic ischemia was induced in eNOS-TG mice and wild-type littermates for 45 minutes, followed by 5 hours of reperfusion.
- Pharmacological inhibitors and activators of soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) were used in wild-type mice.
- The role of sGC and HO-1 in eNOS-TG mice was assessed using specific inhibitors.
Main Results:
- Both strains of eNOS-TG mice exhibited protection from hepatic I-R injury compared to wild-type controls.
- Inhibition of sGC (using ODQ) abolished the protective effects of eNOS overexpression.
- Inhibition of HO-1 (using ZnDPBG) did not affect the protective effects of eNOS overexpression.
Conclusions:
- Hepatic protection in eNOS-TG mice is partially mediated by NO signaling through the sGC-cGMP pathway.
- The protective mechanism appears to be independent of heme oxygenase-1 (HO-1) signal transduction pathways.
