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Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury

Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
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
0363-6135
H2980-H2986
Duranski, Mark R.
f7f42409-b56f-48f5-b0c2-561b96b68305
Elrod, John W.
4303169c-e01e-47e4-95c4-af80e7fe584f
Calvert, John W.
5ae4af7b-d5d2-4689-ba0d-12287c29cbc3
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Lefer, David J.
0a35277a-930b-490a-b397-db94c7fb0a80
Duranski, Mark R.
f7f42409-b56f-48f5-b0c2-561b96b68305
Elrod, John W.
4303169c-e01e-47e4-95c4-af80e7fe584f
Calvert, John W.
5ae4af7b-d5d2-4689-ba0d-12287c29cbc3
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Lefer, David J.
0a35277a-930b-490a-b397-db94c7fb0a80

Duranski, Mark R., Elrod, John W., Calvert, John W., Bryan, Nathan S., Feelisch, Martin and Lefer, David J. (2006) Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury. American Journal of Physiology: Heart and Circulatory Physiology, 291 (6), H2980-H2986. (doi:10.1152/ajpheart.01173.2005). (PMID:16877550)

Record type: Article

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.

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More information

Published date: December 2006
Keywords: nitric oxide, heme oxygenase-1, soluble guanyly cyclase, phosphodiesterase type 5 inhibition, endothelial nitric oxide synthase
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337830
URI: http://eprints.soton.ac.uk/id/eprint/337830
ISSN: 0363-6135
PURE UUID: 474cea12-3420-489d-b27f-4bb88ccf584f
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 04 May 2012 13:09
Last modified: 15 Mar 2024 03:41

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Contributors

Author: Mark R. Duranski
Author: John W. Elrod
Author: John W. Calvert
Author: Nathan S. Bryan
Author: Martin Feelisch ORCID iD
Author: David J. Lefer

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