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

Abstract

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.

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…Classically HDACs deacetylate nucleosome histones and alter the electrostatic properties of chromatin in a manner that represses gene expression (30, 31). Inhibition of HDACs using small molecules such as butyrate, VPA or trichostatin A exerts multiple cardioprotective effects, such as the anti-hypertrophy (32, 33), anti-fibrosis (34, 35), anti-oxidative stress (36), anti-inflammation (37, 38), and anti-apoptosis (39) under non-diabetic conditions, and also anti-DCM (14, 15). Although HDACs are the promising therapeutic target for multiple cardiovascular diseases, the diversity of HDAC isoforms constrain the practice.…”

Drug Repositioning Suggests a Role for the Heat Shock Protein 90 Inhibitor Geldanamycin in Treating COVID-19 Infection

“…[32] This finding is also supported by wortmannin inhibition of coxsackievirus replication in infected mice treated with a histone-deacetylase which induced replication by inhibiting autophagy and inducing apoptosis. [33] Geldanamycin is a benzoquinone with known antimalrial activity. It belongs to a group of drugs called ansamycins.…”

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

“…Accumulating evidence indicates that autophagy is involved in various pathological processes, including cancer and metabolic and neurodegenerative disorders (23,24). Recent studies have shown that autophagy is an important host factor in the regulation of the replication of diverse viruses, such as dengue virus, poliovirus, influenza virus A, and coxsackievirus B3 virus, as well as HBV (25)(26)(27)(28)(29)(30)(31)(32). Evidence indicates that HBV can activate autophagosome formation, which is required for its own replication (28)(29)(30)(31)(32).…”