Calpain regulates CVB3 induced viral myocarditis by promoting autophagic flux upon infection
Calpain regulates CVB3 induced viral myocarditis by promoting autophagic flux upon infection
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钙蛋白酶通过促进感染时自噬流调节 CVB3 诱导的病毒性心肌炎
DOI：
10.1016/j.micinf.2019.07.001
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发表时间：
2020-01-01
影响因子：
5.8
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Meng, Yawen;Sun, Tianle;Xiong, Sidong
钙蛋白酶是钙激活的中性半胱氨酸蛋白酶。已发现钙蛋白酶活性的失调与心血管疾病有关，钙蛋白酶抑制剂被用作心血管疾病的治疗。病毒性心肌炎（VMC）主要由柯萨奇病毒B3组病毒（CVB 3）感染引起。CVB 3病毒感染诱导自噬并劫持该过程以促进其复制。在这项研究中，我们发现钙蛋白酶在VMC影响的心脏中被显著激活。然而，由于心肌炎症和心功能不全，抑制钙蛋白酶的β-内酰胺酶加重了小鼠的VMC症状。在体外抑制钙蛋白酶活性导致LC 3-II的积累和p62/SQSTM 1蛋白表达水平的增加，这表明自噬通量受到钙蛋白酶抑制的损害。在capn 4特异性心肌敲除小鼠体内也观察到钙蛋白酶抑制的这些作用。此外，我们的研究结果提供的证据表明，钙蛋白酶抑制VMC，不像其他心血管疾病，加剧了疾病的症状，损害CVB 3诱导的自噬流量，这可能随后减少病毒自溶酶体降解。我们的研究结果表明，钙蛋白酶抑制剂可能不是一个很好的治疗VMC疾病的临床设置。(C)2019巴斯德研究所。由Elsevier Masson SAS出版。All rights reserved.
Calpains are calcium-activated neutral cysteine proteases. The dysregulation of calpain activity has been found to be related to cardiovascular diseases, for which calpain inhibition is used as a treatment. Viral myocarditis (VMC) is primarily caused by Coxsackievirus group B3 virus infection (CVB3). CVB3 virus infection induces autophagy and hijacks this process to facilitate its replication. In this study, we found that calpain was significantly activated in hearts affected by VMC. However, pharmacologically inhibiting calpain aggravated VMC symptoms in mice due to myocardial inflammation and cardiac dysfunction. The inhibition of calpain activity in vitro led to the accumulation of LC3-II and increased levels of p62/SQSTM1 protein expression, suggesting that autophagic flux was impaired by calpain inhibition. These effects of calpain inhibition were also observed in capn4-specific myocardial knockout mice in vivo. Furthermore, our results provided evidence that calpain inhibition in VMC, unlike other cardiovascular diseases, exacerbated the disease symptom by impairing CVB3-induced autophagic flux, which may subsequently reduce virus autolysosome degradation. Our findings indicated that calpain inhibition may not be a good treatment for VMC disease in a clinical setting. (C) 2019 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.