Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications.
Portal hypertensive (PHT) gastric mucosa increases susceptibility to injury and delayed mucosal healing. It is possible that nitration of ERK by peroxynitrite might alter MAPK (ERK) signaling in PHT gastric mucosa, leading to delayed mucosal healing, since excessive nitric oxide production is implicated in PHT gastric mucosa and MAPK (ERK) signaling induces cell proliferation and leads to gastric mucosal healing in response to injury. Portal hypertension was produced by staged portal vein ligation, and sham-operation (SO) rats served as controls. Lipid peroxide (LPO) and nitrotyrosine increased significantly in PHT gastric mucosa compared with SO rats. ERK activation was impaired in PHT gastric mucosa in response to ethanol injury, whereas no significant difference in the phosphorylation of MEK, an upstream molecule of ERK, was seen between the two groups. The nitration of ERK by peroxynitrite, as detected by the coimmunoprecipitation of ERK and nitrotyrosine, was significantly enhanced in PHT gastric mucosa. Administration of rebamipide, a gastroprotective drug that acts as an oxygen-derived free radical scavenger, significantly decreased LPO and nitrotyrosine as well as the nitration of ERK by peroxynitrite in PHT gastric mucosa, therefore normalizing ERK activation and restoring the gastric mucosal healing response to ethanol injury. Enhanced nitration of ERK by peroxynitrite is involved in the impaired MAPK (ERK) signaling in PHT gastric mucosa. These findings demonstrate a new molecular mechanism in which PHT gastric mucosa is predisposed to injury and impaired healing.
Kinjo
Nao
N
Dept. of Surgery and Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. naokinjo@surg2.med.kyushu-u.ac.jp
Kawanaka
Hirofumi
H
Akahoshi
Tomohiko
T
Yamaguchi
Shohei
S
Yoshida
Daisuke
D
Anegawa
Go
G
Konishi
Kozo
K
Tomikawa
Morimasa
M
Tanoue
Kazuo
K
Tarnawski
Andrzej
A
Hashizume
Makoto
M
Maehara
Yoshihiko
Y
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009566:Nitrates; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013272:Stomach Diseases / Q000150:complications* / Q000188:drug therapy*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D004791:Enzyme Inhibitors; D009566:Nitrates; D015363:Quinolones; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D000431:Ethanol; D014443:Tyrosine; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C052785:rebamipide; D000409:Alanine