Roles of cathepsins in reperfusion-induced apoptosis in cultured astrocytes

被引:33
作者
Takuma, K
Kiriu, M
Mori, K
Lee, E
Enomoto, R
Baba, A
Matsuda, T
机构
[1] Osaka Univ, Grad Sch Pharmaceut Sci, Lab Med Pharmacol, Suita, Osaka 5650871, Japan
[2] Kobe Gakuin Univ, High Technol Res Ctr, Fac Pharmaceut Sci, Dept Analyt Chem, Kobe, Hyogo 6512180, Japan
[3] Kobe Gakuin Univ, High Technol Res Ctr, Fac Pharmaceut Sci, Dept Pharmacol, Kobe, Hyogo 6512180, Japan
[4] Osaka Univ, Grad Sch Pharmaceut Sci, Lab Mol Neuropharmacol, Suita, Osaka 5650871, Japan
关键词
cathepsin; hydrogen peroxide (H2O2); apoptosis; caspase; astrocyte;
D O I
10.1016/S0197-0186(02)00077-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Astrocytic apoptosis may play a role in the central nervous system injury. We previously showed that reperfusion of cultured astrocytes with normal medium after exposure to hydrogen peroxide (H2O2)-containing medium causes apoptosis. This study examines the involvement of the lysosomal enzymes cathepsins B and D in the astrocytic apoptosis. Reperfusion after exposure to H2O2 caused a marked increase in caspase-3 and cathepsin D activities and a marked decrease in cathepsin B activity. Pepstatin A, an inhibitor of cathepsin D, and acetyl-L-aspartyl-L-methionyl-L-glutaminyl-L-aspart-l-aldehyde (Ac-DMQD-CHO), a specific inhibitor of caspase-3, blocked the H2O2-induced decrease in cell viability and DNA ladder formation in cultured rat astrocytes. The (L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl)-L-isoleucyl-L-proline methyl ester (CA074 Me), a specific inhibitor of cathepsin B, did not affect the H2O2-induced cell injury. On the other hand, CA074 Me decreased cell viability with DNA ladder formation when cultured in the presence of Ac-DMQD-CHO. This caspase-independent apoptosis was attenuated by the addition of the cathepsin D inhibitor pepstatin A. Caspase-3 like activity was markedly inhibited by Ac-DMQD-CHO and partially by pepstatin A. Pepstatin A and CA074 Me inhibited cathepsin B and cathepsin D activities, respectively, in the presence and absence of Ac-DMQD-CHO. These results suggest that cathepsins B and D are involved in astrocytic apoptosis: cathepsin D acts as a death-inducing factor upstream of caspase-3 and the caspase-independent apoptosis is regulated antagonistically by cathepsins B and D. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:153 / 159
页数:7
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