Abstract
Increased production of reactive oxygen species (ROS) significantly contributed to the pathogenesis of acute myocardial infarction (AMI). Recent studies suggest that hypoxia upregulated the long noncoding RNA taurine upregulated gene 1 (TUG1). In this study, we explored the functional significance and molecular mechanisms of TUG1/miR-132-3p axis in ischemia-challenged cardiomyocytes. In primary cardiomyocytes challenged with H2O2, expressions of miR-132-3p, TUG1, and other target proteins were measured by RT quantitative PCR or Western blot analysis; cell viability by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay; apoptosis by annexin V and propidium iodide staining; the abundance of acetylated H3K9 or histone deacetylase 3 (HDAC3) within the promoter of target genes by chromatin immunoprecipitation; the direct interaction between miR-132-3p and HDAC3 or TUG1 by luciferase reporter assay. The biological significance of miR-132-3p, TUG1, and HDAC3 was assessed using miR-132-3p mimic, siRNA-targeting TUG1 and HDAC3 inhibitor RGF966, respectively, in H2O2-challenged cells in vitro or ischemia-reperfusion (I/R)-induced AMI in vivo. miR-132-3p was downregulated, whereas TUG1 upregulated in H2O2-challenged cardiomyocytes. Overexpressing miR-132-3p or knocking down TUG1 significantly improved viability, inhibited apoptosis, and reduced ROS production in H2O2-stressed cardiomyocytes in vitro and alleviated I/R-induced AMI in vivo. Mechanistically, TUG1 sponged miR-132-3p and upregulated HDAC3, which reduced the acetylation of H3K9 and epigenetically inhibited expressions of antioxidative genes, including Bcl-xL, Prdx2, and Hsp70. The TUG1/miR-132-3p/HDAC3 axis critically regulates ROS production and the pathogenic development of AMI. Targeting TUG1, upregulating miR-132-3p, or inhibiting HDAC3 may benefit AMI treatment.NEW & NOTEWORTHY Increased production of reactive oxygen species (ROS) significantly contributed to the pathogenesis of acute myocardial infarction (AMI). Recent studies suggest that hypoxia upregulated the long noncoding RNA taurine upregulated gene 1 (TUG1). However, the underlying mechanisms remain elusive. In the present study, we reported for the first time that H2O2 or ischemia-reperfusion-induced TUG1, by sponging microRNA 132-3p, activated histone deacetylase 3, which in turn targeted multiple protective genes, stimulated intracellular ROS accumulation, and aggravated the injury of AMI. Our findings might provide some insight to seek new targets for AMI treatment.