Calpain inhibition protects against virus-induced apoptotic myocardial injury
Calpain inhibition protects against virus-induced apoptotic myocardial injury
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DOI：
10.1128/jvi.75.1.351-361.2001
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发表时间：
2001-01-01
影响因子：
5.4
通讯作者：
Tyler, KL
中科院分区：
文献类型：
--
作者：
DeBiasi, RL;Edelstein, CL;Tyler, KL
病毒性心肌炎是人类发病和死亡的重要原因，缺乏可靠和有效的治疗方法。使用呼肠孤病毒株8B感染新生小鼠，一个良好的表征实验模型的直接病毒诱导的心肌炎，我们现在证明，心肌损伤的结果细胞凋亡。蛋白酶作为细胞凋亡的效应物起着关键作用。半胱氨酸蛋白酶钙蛋白酶的活性在呼肠孤病毒感染的心肌细胞中增加，并且可以被二肽α-酮酰胺钙蛋白酶抑制剂Z-Leu-氨基丁酸-CONH（CH 2）3-吗啉（CX 295）抑制。用CX 295治疗呼肠孤病毒感染的新生小鼠可保护其免受呼肠孤病毒心肌炎的侵害，如以下所述：（i）心肌损伤的组织病理学证据显著减少，（ii）通过末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记鉴定的凋亡性心肌细胞死亡的完全抑制，（iii）血清肌酸磷酸激酶减少，和（iv）体重增加改善。这些发现是钙蛋白酶相关的凋亡细胞死亡途径在病毒性疾病中的重要性的第一个证据。抑制细胞凋亡信号通路可能是治疗病毒性疾病的有效策略，特别是病毒性心肌炎。
Viral myocarditis is an important cause of human morbidity and mortality for which reliable and effective therapy is lacking. Using reovirus strain 8B infection of neonatal mice, a well-characterized experimental model of direct virus-induced myocarditis, we now demonstrate that myocardial injury results from apoptosis. Proteases play a critical role as effecters of apoptosis. The activity of the cysteine protease calpain increases in reovirus-infected myocardiocytes and can be inhibited by the dipeptide alpha-ketoamide calpain inhibitor Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine (CX295). Treatment of reovirus-infected neonatal mice with CX295 protects them against reovirus myocarditis as documented by (i) a dramatic reduction in histopathologic evidence of myocardial injury, (ii) complete inhibition of apoptotic myocardial cell death as identified by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, (iii) a reduction in serum creatine phosphokinase, and (iv) improved weight gain. These findings are the first evidence for the importance of a calpain-associated pathway of apoptotic cell death in viral disease. Inhibition of apoptotic signaling pathways may be an effective strategy for the treatment of viral disease in general and viral myocarditis in particular.