Assessment of a dual regulatory role for NO in liver regeneration after partial hepatectomy: protection against apoptosis and retardation of hepatocyte proliferation.
The role of hepatic nitric oxide (NO) in liver regeneration after partial hepatectomy (PH) was studied in animals carrying a nitric oxide synthase-2 transgene under the control of the phospho(enol)pyruvate carboxykinase promoter. These mice expressed NOS-2 in liver cells under fasting conditions. Liver mass recovery and molecular parameters related to cell proliferation were determined after PH. Preexisting hepatic NO synthesis, as well as NO delivery by NO-donors, impaired early signaling (for example, attenuated NF-kappaB activation and TNF-alpha and IL-6 release). The regenerative process was also impaired as a result of an insufficient proliferative response, but mouse survival after surgery was not compromised. However, NO exerted a protective role against apoptosis in transgenic hepatectomized mice. Local production of NO in liver cells, achieved by hydrodynamic-based transfection with a NOS-2-encoding plasmid, also resulted in delayed liver recovery after PH and also protected against Fas-mediated apoptosis. These data show that sustained presence of NO after PH exerts a dual role: attenuating liver regeneration while efficiently protecting against liver apoptosis.
Zeini
Miriam
M
Instituto de Bioquímica (Centro Mixto CSIC-UCM) and Centro Nacional de Investigaciones Cardiovasculares, Facultad de Farmacia, Universidad, Complutense, Madrid.
Hortelano
Sonsoles
S
Través
Paqui G
PG
Gómez-Valadés
Alicia G
AG
Pujol
Anna
A
Perales
José C
JC
Bartrons
Ramón
R
Boscá
Lisardo
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D002455:Cell Division; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011994:Recombinant Proteins; D014162:Transfection; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D011994:Recombinant Proteins; D019014:fas Receptor; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases