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Am J Physiol Gastrointest Liver Physiol 295: G1016-G1024, 2008. First published September 11, 2008; doi:10.1152/ajpgi.90329.2008
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HORMONES AND SIGNALING

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Nao Kinjo,1 Hirofumi Kawanaka,1 Tomohiko Akahoshi,1 Shohei Yamaguchi,2 Daisuke Yoshida,2 Go Anegawa,1 Kozo Konishi,2 Morimasa Tomikawa,1 Kazuo Tanoue,1 Andrzej Tarnawski,3 Makoto Hashizume,2 and Yoshihiko Maehara1

1Department of Surgery and Science, 2Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan; 3Department of Medicine, Veterans Affairs Long Beach Healthcare System and the University of California, Irvine, California

Submitted 8 May 2008 ; accepted in final form 28 August 2008

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.

rebamipide; oxidative stress; MAP kinase


Address for reprint requests and other correspondence: N. Kinjo, Dept. of Surgery and Science, Graduate School of Medical Sciences, Kyushu Univ., 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: naokinjo{at}surg2.med.kyushu-u.ac.jp)






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