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

Abstract

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.

Regulation of Apoptosis by Enteroviruses

“…miRNAs are a class of small, single-stranded noncoding RNAs widely found in eukaryotes that block the translation of their target mRNAs via posttranscriptional regulation, ultimately inhibiting target gene expression (Tang et al, 2016). In addition to engaging in the abovementioned mechanisms, CVB3 can target miRNA-34a in host cells to downregulate the histone deacetylase SIRT1, consequently increasing Bax expression, inhibiting Bcl-2 expression and inducing apoptosis (Jiang et al, 2019). Furthermore, p53dependent apoptosis can be promoted by upregulation of the expression of the histone deacetylase HDAC1 via miRNA-34a (Zhou et al, 2015).…”

“…Enteroviruses regulate miRNAs to induce apoptosis. Apoptosis induced by enterovirus infection is associated with the regulation of microRNAs (miRNAs)(Chang et al, 2015;Jiang et al, 2019). The red dotted line indicates the site of enteroviral action, and the red solid arrows indicate the up-or downregulation of the expression of each protein.…”

Clinical significance of miR‑181a in patients with neonatal sepsis and its regulatory role in the lipopolysaccharide‑induced inflammatory response

“…Numerous studies have indicated the pivotal roles of miRNAs in the initiation and development of various human diseases, including malignancies (22), metabolic diseases (23) and cardiovascular diseases (24). In sepsis, there are also functional miRNAs that are linked to the progression of the disease by the regulation of inflammatory response, such as miR-150 (25) and miR-27a (26), e.g.…”

Dysregulated CD4+ T Cells and microRNAs in Myocarditis

“…miR-19b contributed to cardiac arrhythmia through repression of gap junction protein α1 (GJA1) in a mouse model of VMC (154). miR-34a promoted cardiomyocyte apoptosis by downregulating sirtuin 1 (SIRT1), an inhibitory factor to p53-dependent apoptosis (155). miR-141-3p alleviated the inflammatory response by inhibiting signal transducer and activator of transcription 4 (STAT4) in mice with EAM (156).…”