Inhibition of Histone Deacetylase Activity Aggravates Coxsackievirus B3-Induced Myocarditis by Promoting Viral Replication and Myocardial Apoptosis.
Inhibition of Histone Deacetylase Activity Aggravates Coxsackievirus B3-Induced Myocarditis by Promoting Viral Replication and Myocardial Apoptosis.
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DOI：
10.1128/jvi.01028-15
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发表时间：
2015-10
影响因子：
5.4
通讯作者：
Xiong S
中科院分区：
文献类型：
--
作者：
Zhou L;He X;Gao B;Xiong S
病毒性心肌炎是一种以心肌过度炎症为特征的严重临床疾病，最常见的是柯萨奇B3病毒（CVB3）。最近的研究表明，通过抑制组蛋白去乙酰化酶（HDAC）活性来调节蛋白质乙酰化水平可以调节炎症反应，并有望成为几种炎症性疾病的治疗方法。然而，HDAC活性在病毒性心肌炎中的作用尚不完全清楚。在此，我们旨在探讨HDAC活性在病毒性心肌炎中的作用及其潜在机制。用HDAC抑制剂（HDACI）亚甲基苯胺羟肟酸（SAHA）或曲古霉素A （TSA）治疗cvb3感染的BALB/c小鼠。我们发现抑制HDAC活性加重了而不是减轻了cvb3诱导的心肌炎的严重程度，这与我们的预期相反。HDACI治疗的心肌炎加重似乎不是由炎症反应升高引起的，而是由CVB3复制增加引起的。此外，研究显示CVB3复制的增加与hdaci增强的自噬体形成密切相关。wortmannin或ATG5短发夹RNA抑制自噬体形成可显著抑制hdaci增加的CVB3复制。增加的病毒复制随后增加了cvb3诱导的心肌凋亡。相反，抗病毒药物利巴韦林抑制CVB3复制和随后的心肌凋亡可显著逆转hdaci加重的病毒性心肌炎。总之，我们阐明抑制HDAC活性增加CVB3复制和随后的心肌凋亡，导致病毒性心肌炎加重。对于感染（或合并感染）CVB3的患者，应考虑使用HDACI可能产生的不良后果。病毒性心肌炎以心肌过度炎症为特征，主要由CVB3引起。抑制HDAC活性最初被认为是一种强大的抗癌治疗策略，最近发现与炎症反应的调节有关。HDACI已在几种炎症性疾病的动物模型中被证明是有效的。因此，我们假设抑制HDAC活性也可以预防cvb3诱导的病毒性心肌炎。令人惊讶的是，我们发现抑制HDAC活性可增强心肌自噬体的形成，从而导致CVB3病毒复制升高，随后心肌凋亡增加。抑制HDAC后，病毒性心肌炎最终加重而非减轻。总之，我们阐明了HDAC活性在病毒性心肌炎中的作用。此外，鉴于HDACI在临床前和临床治疗中的重要性，在感染病毒（包括CVB3）的患者中，应仔细评估HDACI可能产生的不利影响。
Viral myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3), is a serious clinical condition characterized by excessive myocardial inflammation. Recent studies suggest that regulation of protein acetylation levels by inhibiting histone deacetylase (HDAC) activity modulates inflammatory response and shows promise as a therapy for several inflammatory diseases. However, the role of HDAC activity in viral myocarditis is still not fully understood. Here, we aim to investigate the role of HDAC activity in viral myocarditis and its underlying mechanism. CVB3-infected BALB/c mice were treated with the HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA). We found inhibition of HDAC activity aggravated rather than ameliorated the severity of CVB3-induced myocarditis, which was contrary to our expectations. The aggravated myocarditis by HDACI treatment seemed not to be caused by an elevated inflammatory response but by the increased CVB3 replication. Further, it was revealed that the increased CVB3 replication was closely associated with the HDACI-enhanced autophagosome formation. Inhibition of autophagosome formation by wortmannin or ATG5 short hairpin RNA dramatically suppressed the HDACI-increased CVB3 replication. The increased viral replication subsequently elevated CVB3-induced myocardial apoptosis. Conversely, inhibition of CVB3 replication and ensuing myocardial apoptosis by the antiviral drug ribavirin significantly reversed the HDACI-aggravated viral myocarditis. In conclusion, we elucidate that the inhibition of HDAC activity increases CVB3 replication and ensuing myocardial apoptosis, resulting in aggravated viral myocarditis. Possible adverse consequences of administering HDACI should be considered in patients infected (or coinfected) with CVB3. IMPORTANCE Viral myocarditis, which is most prevalently caused by CVB3, is characterized by excessive myocardial inflammation. Inhibition of HDAC activity was originally identified as a powerful anti-cancer therapeutic strategy and was recently found to be implicated in the regulation of inflammatory response. HDACI has been demonstrated to be efficacious in animal models of several inflammatory diseases. Thus, we hypothesize that inhibition of HDAC activity also protects against CVB3-induced viral myocarditis. Surprisingly, we found inhibition of HDAC activity enhanced myocardial autophagosome formation, which led to the elevated CVB3 viral replication and ensuing increased myocardial apoptosis. Viral myocarditis was eventually aggravated rather than ameliorated by HDAC inhibition. In conclusion, we elucidate the role of HDAC activity in viral myocarditis. Moreover, given the importance of HDACI in preclinical and clinical treatments, the possible unfavorable effect of HDACI should be carefully evaluated in patients infected with viruses, including CVB3.