Abstract
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.
Highlights
Viral myocarditis, which is often caused by coxsackievirus B3 (CVB3), is a serious clinical disorder characterized by excessive myocardial inflammation
Valproic acid (VPA) treatment attenuates CVB3-induced myocarditis in mice To investigate the effect of VPA on CVB3-induced viral myocarditis, mice were first infected with CVB3 or mock and treated daily with either VPA (i.p., 250 mg/kg) or vehicle from day 0 to day 7 after infection
Mice receiving phosphate-buffered saline (PBS) alone developed no sign of viral myocarditis, whereas the signs of viral myocarditis were apparent in CVB3-infected mice, including weakness, irritability, lethargy and weight loss, with 40 % of mice died on day 14 postinfection (Fig. 1a)
Summary
Viral 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. It has been shown that several T helper (Th) subsets, such as Th17 and Treg cells, are involved in the pathogenesis of viral myocarditis [4,5,6]. Histone deacetylases (HDACs) are part of a vast family of enzymes involved in chromatin remodeling that play a key role in the differentiation and immune function of T cells [10, 11]. Administration of VPA could decrease disease incidence and severity in collagen induced mouse arthritis through effects on the production and function of Treg cells [15]. It is reasonable to hypothesize that HDAC inhibitor plays a protective role in viral myocarditis. Our findings suggest that VPA may be a promising therapeutic strategy for treating viral myocarditis
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