Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications
Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications
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DOI：
10.1152/ajpgi.90329.2008
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发表时间：
2008-11-01
影响因子：
4.5
通讯作者：
Maehara, Yoshihiko
中科院分区：
文献类型：
--
作者：
Kinjo, Nao;Kawanaka, Hirofumi;Maehara, Yoshihiko
门脉高压症(PHT)胃粘膜损伤易感性增加，粘膜愈合延迟。过氧亚硝酸硝化ERK可能改变了PHT胃粘膜MAPK(ERK)信号转导途径，导致胃粘膜愈合延迟，因为PHT胃粘膜产生过多的一氧化氮，而MAPK(ERK)信号诱导细胞增殖，导致胃粘膜损伤后的修复。采用门静脉分期结扎法建立门静脉高压模型，假手术(SO)大鼠作为对照。与SO大鼠相比，PHT大鼠胃粘膜过氧化脂质(LPO)和硝基酪氨酸显著升高。乙醇损伤后，PHT胃粘膜ERK活性降低，而ERK上游分子MEK的磷酸化水平在两组间无显著差异。用ERK和硝基酪氨酸的免疫共沉淀法检测，在PHT胃粘膜中，过氧亚硝酸盐对ERK的硝化作用显著增强。给予氧自由基清除剂瑞巴比特可显著降低PHT大鼠胃粘膜LPO和硝基酪氨酸含量以及过氧亚硝酸盐对ERK的硝化作用，从而使ERK活性恢复正常，恢复胃粘膜对乙醇损伤的修复反应。过氧亚硝酸盐对ERK的硝化增强参与了PHT胃粘膜MAPK(ERK)信号的受损。这些发现表明了PHT胃粘膜易于损伤和愈合受阻的新的分子机制。
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.