Histone deacetylase inhibitors suppress coxsackievirus B3 growth in vitro and myocarditis induced in mice

Shim, Seung‐Hyuk; Jh, Park; Mb, Ye; Jh, Nam

doi:10.4149/av_2013_04_462

Cited by 10 publications

(8 citation statements)

References 13 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aside from SIRT1, we examined the effect of HDAC1—a member of the classic HDAC family, whose members are located in the nucleus—on p53 acetylation. Shim et al have found that inhibition of HDAC activity reduces CVB3 replication, and Zhou et al reported that inhibition of HDAC activity by hydroxamic acid or TSA reduces cardiomyocyte apoptosis. We can speculate that HDAC1 promotes the CVB3‐induced cardiomyocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

microRNA‐34a aggravates coxsackievirus B3‐induced apoptosis of cardiomyocytes through the SIRT1‐p53 pathway

Jiang

et al. 2019

Journal of Medical Virology

View full text Add to dashboard Cite

Viral myocarditis is inflammation of the myocardium mainly caused by a viral infection, and coxsackievirus B3 (CVB3) infection is one of the most common. It is well known that cardiomyocyte apoptosis is involved in the pathogenesis of viral myocarditis. microRNAs (miRNAs, miRs) are endogenous noncoding oligoribonucleotides involved in various pathological conditions, and miR-34a is one of the miRNAs causing apoptosis. Whether miR-34a participates in cardiomyocyte apoptosis during CVB3 infection and the underlying mechanisms is still unclear. In this in vitro study, we found that miR-34a expression increased in cardiomyocytes after CVB3 infection.Furthermore, we found that CVB3 infection augmented histone deacetylase 1 (HDAC1) and Bax expression while inhibiting sirtuin 1 (SIRT1) and Bcl-2 expression, along with the acetylated p53 (Ac-p53) upregulation in cardiomyocytes. The abovementioned phenomenon was reversed by a miR-34a inhibitor after CVB3 infection. In addition, the Ac-p53 amount increased in CVB3-infected cardiomyocytes, and SRT1720 and trichostatin A (TSA) pretreatment decreased Ac-p53 levels. After pifithrin-α pretreatment of CVB3-infected cardiomyocytes, the protein expression level of HDAC1 decreased while that of SIRT1 increased. Moreover, miR-34a expression and CVB3-induced apoptosis of cardiomyocytes were attenuated by pretreatment with SRT1720, TSA, or pifithrin-α, accompanied with Bax downregulation and Bcl-2 upregulation. In summary, these data indicate that miR-34a induces cardiomyocyte apoptosis by downregulating SIRT1, and the activation of the SIRT1-p53 pathway contributes to CVB3-induced apoptosis of cardiomyocytes. Thus, miR-34a might serve as a potential therapeutic target because it promotes cardiomyocyte apoptosis through the SIRT1-p53 signaling pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

microRNA‐34a aggravates coxsackievirus B3‐induced apoptosis of cardiomyocytes through the SIRT1‐p53 pathway

Jiang

et al. 2019

Journal of Medical Virology

View full text Add to dashboard Cite

show abstract

“…Therefore, VPA may function through the HDAC inhibitory activity to attenuate inflammation in viral myocarditis. In addition, Shim et al reported that Histone deacetylase inhibitors Trichostatin A could suppress CVB3 replication in Hela cells in vitro, and subsequently reduces CVB3 titers in the heart and protects mice from myocarditis [ 17 ]. In our study, we also observed significantly decreased CVB3 replication in heart tissues in vivo, suggesting that decreased viral replication is also necessary for VPA-mediated amelioration of viral myocarditis.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is reasonable to hypothesize that HDAC inhibitor plays a protective role in viral myocarditis. One study showed that HDAC inhibitors could suppress CVB3 growth in vitro and CVB3-induced myocardial injury in vivo [ 17 ]. However, the role and the detailed mechanism of VPA in viral myocarditis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Valproic acid ameliorates coxsackievirus-B3-induced viral myocarditis by modulating Th17/Treg imbalance

Haibin¹,

Gao²

2016

Virol J

View full text Add to dashboard Cite

BackgroundViral myocarditis, which is often caused by coxsackievirus B3 (CVB3), is a serious clinical disorder characterized by excessive myocardial inflammation. Valproic acid (VPA) is described as a histone deacetylase inhibitor that has anti-inflammatory effects in several inflammatory diseases. However, the role and the detailed mechanism of VPA in viral myocarditis remain unclear.MethodsExperimental CVB3-induced myocarditis was induced in mice by intraperitoneally (i.p.) infected with CVB3. VPA was i.p. administered from day 0 to day 7. The survival, body weight loss, and myocarditis severity of mice were recorded. Th17 and Treg cells in spleen were analyzed by flow cytometry. Th17/Treg cell-related cytokine expressions were quantified by ELISA. The effect of VPA on Th17 and Treg cells differentiation was examined in vitro and in vivo.ResultsAdministration of VPA significantly attenuated the clinical severity of myocarditis, and the overall mortality from CVB3-induced myocarditis. The infiltration of Th17 and Treg cells, as well as the serum level of related cytokines (IL-17A and IL-10), were increased in CVB3 infected mice. In addition, VPA decreased the percentage of splenic Th17 cells while increased the percentage of Treg cells. Moreover, VPA downregulated the expression of IL-17A and upregulated IL-10 in serum and heart tissues of CVB3 infected mice. Additionally, VPA directly inhibited the differentiation of Th17 cells and promoted both the differentiation and suppressive function of Treg cells in vitro and in vivo.ConclusionsOur results suggest that VPA may thus be a promising strategy in the therapy of viral myocarditis.

show abstract

“…This result is in conflict with the Shim et al study in which TSA suppressed the CVB3 replication at 24 h p.i. in HeLa cells and protected against CVB3-induced myocardial injury in vivo ( 37 ). The reason for this apparent discrepancy is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for this apparent discrepancy is unclear. However, we used the CVB3 Nancy strain in the current study, whereas Shim et al used the Woodruff strain ( 37 ). The different CVB3 strain might account for the discrepancy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Histone Deacetylase Activity Aggravates Coxsackievirus B3-Induced Myocarditis by Promoting Viral Replication and Myocardial Apoptosis

Zhou

Gao

et al. 2015

J Virol

View full text Add to dashboard Cite

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.

show abstract

Histone deacetylase inhibitors suppress coxsackievirus B3 growth in vitro and myocarditis induced in mice

Cited by 10 publications

References 13 publications

microRNA‐34a aggravates coxsackievirus B3‐induced apoptosis of cardiomyocytes through the SIRT1‐p53 pathway

microRNA‐34a aggravates coxsackievirus B3‐induced apoptosis of cardiomyocytes through the SIRT1‐p53 pathway

Valproic acid ameliorates coxsackievirus-B3-induced viral myocarditis by modulating Th17/Treg imbalance

Inhibition of Histone Deacetylase Activity Aggravates Coxsackievirus B3-Induced Myocarditis by Promoting Viral Replication and Myocardial Apoptosis

Contact Info

Product

Resources

About