This study investigates whether
KMUP-1 improves hepatic
ischemia-reperfusion (I/R) and hypoxic cell injury via inhibiting Nox2- and
reactive oxygen species (ROS)-mediated pro-
inflammation. Rats underwent
ischemia by occlusion of the portal vein and hepatic artery for 45 minutes. Reperfusion was allowed for 4 h. Serum was used for analysis of
aspartate aminotransferase (AST) and
alanine aminotransferase (ALT).
DNA extracted from liver homogenate was analyzed by electrophoresis to observe the fragmentation. Lipid peroxidation (LPO) was evaluated by measuring
thiobarbituric acid-reactive substances (
TBARS). NO and ROS contents were measured using
Griess reagent and 2′-7′-dichlorofluorescein, respectively.
Proteins levels were visualized by Western blotting. Liver damage was observed under a microscope. Intravenous
KMUP-1 (0.25, 0.5 and 1 mg/kg) reduced I/R-induced ALT and AST levels, DNA fragmentation, ROS and
malondialdehyde (MDA) and restored the NO levels of I/R rats.
KMUP-1 protected the liver architecture from worsening of damage and focal sinusoid congestion, increased endothelium
NO synthase (eNOS),
guanosine 3', 5'cyclic monophosphate (cGMP),
protein kinase G (PKG) and the
B-cell lymphoma 2/
Bcl-2-associated X protein (Bcl-2/Bax) ratio, attenuated
phosphodiesterase 5A (PDE-5A) and cleaved
caspase-3 expression in I/R-liver. In hypoxic HepG2 cells,
KMUP-1 increased cGMP/PKG, restored
peroxisome proliferator-activated receptor-gamma (
PPAR-gamma) and decreased matrix metalloproteinases-9 (MMP-9),
Rho kinase II (ROCK II),
hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelium
growth factor (
VEGF).
KMUP-1 protects liver from I/R-injury and hypoxic hepatocytes from apoptosis-associated
free radical generation and pro-
inflammation by restoring/increasing NO/cGMP/
PPAR-gamma, reducing ROS/Nox2 and inhibiting ROCKII/
MMP-9.