Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo

被引:97
作者
Harada, C
Nakamura, K
Namekata, K
Okumura, A
Mitamura, Y
Iizuka, Y
Kashiwagi, K
Yoshida, K
Ohno, S
Matsuzawa, A
Tanaka, K
Ichijo, H
Harada, T
机构
[1] Tokyo Metropolitan Inst Neurosci, Dept Mol Neurobiol, Fuchu, Tokyo 1838526, Japan
[2] Tokyo Med & Dent Univ, Lab Mol Neurosci, Sch Biomed Sci, Tokyo, Japan
[3] Tokyo Med & Dent Univ, Med Res Inst, Tokyo, Japan
[4] Sapporo Med Univ, Sch Med, Dept Ophthalmol, Sapporo, Hokkaido, Japan
[5] Univ Yamanashi, Fac Med, Dept Ophthalmol, Yamanashi, Japan
[6] Hokkaido Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Sapporo, Hokkaido, Japan
[7] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Cell Signaling, Tokyo, Japan
[8] Japan Sci & Technol Corp, CREST, Tokyo, Japan
[9] Ctr Excellence Program, Tokyo, Japan
[10] Japan Sci & Technol Corp, Precursory Res Embryon Sci & Technol, Kawaguchi, Japan
基金
日本学术振兴会;
关键词
D O I
10.2353/ajpath.2006.050765
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild type mice. Interestingly, ischemia induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL,positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H2O2-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could he useful for the treatment of neurodegenerative diseases including glaucoma.
引用
收藏
页码:261 / 269
页数:9
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