Abstract
Histone deacetylases (HDACs) and microRNAs (miRs) have been reported to exert pivotal roles on the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). Therefore, the present study was performed to define the underlying role of HDAC4 and miR-206 in the pathological process of MIRI. An IRI rat model was established. The interaction between HDAC4 and the promoter region of miR-206 was determined using ChIP, and that between miR-206 and mitogen-activated protein kinase kinase kinase 1 (MEKK1) was determined using dual luciferase reporter gene assay. After the loss- or gain-of-function assay in cardiomyocytes, western blot analysis, RT-qPCR, TUNEL, and ELISA assay were performed to define the roles of HDAC4, miR-206, and MEKK1. Up-regulation of HDAC4 and down-regulation of miR-206 occurred in rat myocardial tissues and cardiomyocytes in MIRI. HDAC4 down-regulation or miR-206 up-regulation contributed to reduced cell apoptosis and the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA), while elevating the superoxide dismutase (SOD) and glutathione (GSH) contents. Meanwhile, HDAC4 silencing promoted the expression of miR-206, which targeted and negatively regulated MEKK1. Then inhibition of JNK phosphorylation reduced the cardiomyocyte apoptosis to alleviate MIRI. Coherently, HDAC4 silencing could up-regulate the expression of miR-206 to reduce cardiomyocyte apoptosis and inhibit oxidative stress, and exerting a protective effect on MIRI via the MEKK1/JNK pathway.
Highlights
Myocardial ischemia-reperfusion injury (MIRI), a manifestation of cardiomyocyte apoptosis induced by ischemia-reperfusion (IR), is a crucial cause for myocardial damage and subsequent heart failure, resulting in high morbidity and mortality worldwide [1]
histone deacetylase 4 (HDAC4) was up-regulated in cardiomyocytes after MIRI and HDAC4 silencing could alleviate myocardial injury in vivo To explore the role of HDAC4 in IRI, we first established an IRI rat model
Analysis of the myocardial tissues with 2,3,5-triphenyltetrazoliumchloride (TTC) staining (Fig. 1A) demonstrated that the presence of an infarct area in the area at risk (AAR) was much higher in the IRI rats than that in the sham-operated rats, while the percentage of infarct area in AAR was found to be reduced in short hairpin RNA-HDAC4-treated IRI rats compared to IRI rats
Summary
Myocardial ischemia-reperfusion injury (MIRI), a manifestation of cardiomyocyte apoptosis induced by ischemia-reperfusion (IR), is a crucial cause for myocardial damage and subsequent heart failure, resulting in high morbidity and mortality worldwide [1]. The inhibition of histone deacetylase 4 (HDAC4) has been demonstrated to confer significant cardioprotective effects against hypoxic injury [6]. HDAC4 down-regulation functions as a critical stimulant for myocardial repair [7].On the other hand, a study has demonstrated that HDAC4 is a target of microRNA-206 (miR-206) in the regulation of myogenic differentiation [8]. MiR-206 is implicated in the regulation of skeletal muscle differentiation via suppression of multiple factors of the c-Jun N-terminal kinase (JNK)/mitogenactivated kinase-like protein (MAPK) pathway such as mitogenactivated protein kinase kinase kinase 1 (MEKK1) and MAP kinase kinase 7 [16], which is highly suggestive of a novel regulatory mechanism involving HDAC4, miR-206, and the MEKK1/JNK pathway. JNK is a protein kinase that can be activated by stress or Received: 3 April 2021 Revised: 29 June 2021 Accepted: 26 July 2021
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