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1 Dept. of Medicine, Div. of Cardiology, Albert Einstein College of Medicine, Bronx, New York, United States
2 Dept. of Medicine, Div. of Cardiology and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States
3 Medicine, Boston University Medical Center, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: dlefer{at}aecom.yu.edu.
Previous studies have shown that endothelial nitric oxide synthase (eNOS) derived nitric oxide (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 transgenic mice to 45 min of hepatic ischemia and 5 hr of reperfusion. Both strains were protected from hepatic I-R injury compared to wild-type littermates. Since the mechanism for this protection is still unclear, additional studies were performed using inhibitors and activators of both soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) enzymes. Blocking sGC (ODQ) and HO-1 (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, while 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.
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