Simultaneous abrogation of NOS-2 and COX-2 activities is lethal in partially hepatectomised mice.
OBJECTIVE
We have investigated the role of the nitric oxide (NO) and prostaglandins (PGs), respectively, synthesized by nitric oxide synthase 2 (NOS-2) and cyclooxygenase-2 (COX-2), in the outcome of liver regeneration after partial hepatectomy (PH).


METHODS
Liver mass recovery and molecular parameters related to cell proliferation and apoptotic death have been determined.


RESULTS
NOS-2 and COX-2 are normally both expressed in the remnant liver after PH, and inhibition of either one delays regeneration. We found, however, that simultaneous suppression of the activities of NOS-2 (by gene knockout) and COX-2 (by pharmacological inhibition) resulted in animal death between 24 and 72 h after PH. Analysis of liver mass recovery and molecular parameters related to cell proliferation and apoptotic death revealed increased liver-cell apoptosis and an insufficient proliferative response. Broad-specificity caspase inhibitors, such as z-Val-Ala-Asp.fmk (z-VAD), or administration of NO-donors, rescued animals from death, revealing a critical apoptotic bias at this stage of proliferation.


CONCLUSIONS
These findings demonstrate that simultaneous signaling by NO and prostaglandins plays an important role in the mechanism of liver regeneration after PH by protecting the remnant tissue from apoptotic death.
Zeini
Miriam
M
Instituto de Bioquímica (Centro Mixto CSIC-UCM), Facultad de Farmacia, Universidad Complutense, 28040, Madrid, Spain.
Hortelano
Sonsoles
S
Través
Paqui G
PG
Martín-Sanz
Paloma
P
Boscá
Lisardo
L
D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D051546:Cyclooxygenase 2; D003643:Death; D006498:Hepatectomy / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics*
D029742:Caenorhabditis elegans Proteins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C400703:nos-2 protein, C elegans; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases