Defective mitogen-activated protein kinase (ERK2) signaling in gastric mucosa of portal hypertensive rats: potential therapeutic implications.
Portal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. PHT gastric mucosa has numerous abnormalities such as reduced mucosal potential differences, reduced surface oxygenation, and increased susceptibility to injury caused by alcohol, aspirin, and other noxious factors. Because such mucosal injury is initially mediated by oxygen free radicals, and because mitogen-activated protein (MAP) kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we show that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from the underlying and continual oxidative state associated with portal hypertension, and is ameliorated by inhibiting MKP-1. Furthermore, we found that supplementing vitamin E, a free radical scavenger, reduces the oxidative state in PHT gastric mucosa, normalizes MKP-1 expression, and thereby reverses impairment of oxidative stress-induced ERK2 activation. Finally, we show that orally administered vitamin E completely reverses the increased susceptibility of PHT gastric mucosa to alcohol injury. Our findings point to a new molecular and mechanistic basis for PHT gastropathy and provide a new therapeutic modality for protection of PHT gastric mucosa.
Kawanaka
H
H
Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.
Tomikawa
M
M
Jones
M K
MK
Szabo
I L
IL
Pai
R
R
Baatar
D
D
Tsugawa
K
K
Sugimachi
K
K
Sarfeh
I J
IJ
Tarnawski
A S
AS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D018797:Cell Cycle Proteins; D004198:Disease Susceptibility; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006975:Hypertension, Portal / Q000503:physiopathology* / Q000628:therapy; D017874:Immediate-Early Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015398:Signal Transduction; D013272:Stomach Diseases / Q000139:chemically induced / Q000473:pathology; D014638:Vanadates / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
D000975:Antioxidants; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D016877:Oxidants; D011281:Pregnatrienes; C074965:U 74389F; D014810:Vitamin E; D000431:Ethanol; D014638:Vanadates; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins