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 o f liver cirrhosis. PHT gastric mucosa has numerous abnormalities such as re duced mucosal potential differences, reduced surface oxygenation, and incre ased 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) protect s against cellular stress and induces cell proliferation, we postulated tha t oxidative stress-induced ERK2 activation is defective in PHT gastric muco sa. Here we show that in PHT gastric mucosa, ERK2 activation by oxidative s tress is impaired. This impairment is mediated by overexpression of MAP kin ase pbosphatase-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 fre e radical scavenger, reduces the oxidative state in PHT gastric mucosa, nor malizes MKP-1 expression, and thereby reverses impairment of oxidative stre ss-induced ERK2 activation. Finally, we show that orally administered vitam in E completely reverses the increased susceptibility of PHT gastric mucosa to alcohol injury. Our findings point to a new molecular and mechanistic b asis for PHT gastropathy and provide a new therapeutic modality for protect ion of PHT gastric mucosa.