Role of nitric oxide synthesized by nitric oxide synthase 2 in liver regeneration.
OBJECTIVE
Nitric oxide synthase 2 (NOS2) is expressed during liver regeneration after a partial hepatectomy (PHx); NOS2 subsequently synthesizes nitric oxide (NO). However, the role of NOS2-synthesized NO in post-PHx liver regeneration remains unclear. We investigated the role of NOS2-synthesized NO in liver regeneration.


METHODS
NOS2 knockout (NOS2-KO) mice and control mice were subjected to PHx. Liver mass recovery and serum alanine aminotransferase (ALT) levels were then evaluated. The expressions of Ki-67 and single-strand DNA were also evaluated in remnant liver specimens. Differences in the gene expression profiles of the two groups of remnant liver specimens were analysed using a microarray and were validated using a reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
In NOS2-KO mice, liver regeneration was delayed and apoptosis and serum ALT levels were higher than the levels in the control mice. A microarray study and RT-PCR revealed that heat shock protein 70 family (HSP70 family), haeme oxygenase 1 (Hmox1), neuropilin 1 (Nrp1) and epidermal growth factor receptor (EGFR) were downregulated in NOS2-KO mice.


CONCLUSIONS
NOS2-synthesized NO may improve hepatocyte viability through the induction of the HSP70 family and Hmox1 and may sensitize the remnant liver to growth factors through the induction of Nrp1 and EGFR post-PHx.
Kumamoto
Takafumi
T
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Togo
Shinji
S
Ishibe
Atsushi
A
Morioka
Daisuke
D
Watanabe
Kazuteru
K
Takahashi
Takuji
T
Shimizu
Tetsuya
T
Matsuo
Ken-ichi
K
Kubota
Toru
T
Tanaka
Kuniya
K
Nagashima
Yoji
Y
Kawai
Jun
J
Hayashizaki
Yoshihide
Y
Shimada
Hiroshi
H
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D020868:Gene Silencing; D006498:Hepatectomy; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008115:Liver Regeneration / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis
D015415:Biomarkers; D019394:Ki-67 Antigen; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse