Submitted on May 8, 2008
Revised on July 24, 2008
Accepted on August 28, 2008
Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications
Nao Kinjo1*, Hirofumi Kawanaka1, Tomohiko Akahoshi2, Shohei Yamaguchi1, Daisuke Yoshida1, Go Anegawa2, Kozo Konishi, Morimasa Tomikawa, Kazuo Tanoue2, Andrzej Tarnawski3, Makoto Hashizume1, and Yoshihiko Maehara
1 Graduate School of Medical Sciences, Kyushu University
2 Graduate school of Medical Sciences, Kyushu University
3 University of California, Irvine
* To whom correspondence should be addressed. E-mail: naokinjo{at}surg2.med.kyushu-u.ac.jp.
Background & Aims: 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. Methods: Portal hypertension was produced by staged portal vein ligation and sham-operation (SO) rats served as controls. Results: Lipid peroxide (LPO) and nitrotyrosine increased significantly in PHT gastric mucosa in comparison to 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 co-immunoprecipitation of ERK and nitrotyrosine, was significantly enhanced in PHT gastric mucosa. Administration of rebamipide, a gastroprotective drug that acts as an oxygen 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. Conclusions: 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.
