Background. This study is aimed at effectively investigating the role of coagulation factor II thrombin receptor like 2 (F2RL2) in myocardial infarction (MI) as well as the upstream regulatory miRNA and lncRNA. Methods. Regulatory genes of F2RL2 were analyzed using StarBase and verified by dual-luciferase reporter assay. The MI mouse model was established. The left ventricular ejection fraction (EF) and fractional shortening (FS) were examined by echocardiography. The infarct area, pathological changes, and cell apoptosis in mouse myocardial tissue were evaluated using triphenyltetrazolium chloride and Evans blue, hematoxylin-eosin, and TUNEL staining assays. Oxygen-glucose deprivation- (OGD-) induced human cardiac myocytes (HCMs) were cultured and transfected. The cell viability, proliferation, and apoptosis were determined by CCK-8, EdU staining, and flow cytometry assays. The expressions of F2RL2, miR-582-5p, and nuclear paraspeckle assembly transcript 1 (NEAT1) in myocardial tissues and HCMs were quantified by qRT-PCR or Western blot. Results. NEAT1 sponged miR-582-5p which targeted F2RL2. NEAT1 and F2RL2 were highly expressed while miR-582-5p was lowly expressed in MI mice. F2RL2 downregulation prevented the reduction in EF and SF and the elevation in infarct area and cell apoptosis of MI mice. Both F2RL2 and NEAT1 downregulations reversely modulated the decreased viability and proliferation and the increased apoptosis of OGD-induced HCMs, while miR-582-5p inhibitor did oppositely. NEAT1 silencing upregulated miR-582-5p level but downregulated F2RL2 level. miR-582-5p inhibitor upregulated the F2RL2 level. The role of NEAT1 silencing in OGD-induced HCMs was reversed by miR-582-5p inhibitor whose effect was further offset by F2RL2 downregulation. Conclusion. NEAT1 downregulation ameliorates MI by regulating the miR-582-5p/F2RL2 axis, providing novel biomarkers for MI treatment.
Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study is to analysis the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Material and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP and ROS were analyzed. Results: 7 possible pathogenic mutations: MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G and MT-TT 15927G>A were identified in DCM group but absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs, and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number, whereas a markedly increased in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which shaded novel insight into the pathophysiology of DCM that was manifestated by mitochondrial dysfunction.
Histone deacetylase enzymes (HDACs) regulate protein acetylation. HDAC1 is known to enhance ischemia/reperfusion (I/R) injury, but its underlying mechanism(s) of action have not been defined. Here, in vivo mouse models of myocardial I/R were used to investigate the role of HDAC1 during I/R myocardial injury. We show that HDAC1 enhances the inflammatory responses of I/R mice. Using a constructed macrophage H/R (hypoxia/ regeneration) injury model (Raw264.7 cells), we identified Nur77 as a HDAC1 target in macrophages. Nur77 deficient macrophages failed to downregulate IDH1 (isocitrate dehydrogenase 1) and accumulated succinic acid and other tricarboxylic acid (TCA) cycle-derived metabolites in a glutamine-independent manner. These data show that the inhibition of HDAC1 ameliorates H/R-inflammation in macrophages through the regulation of Nur77 and the TCA cycle.
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells (PAEC) and pulmonary artery smooth muscle cells (PASMC). To explore the potential mechanism of miR-193-3p in PAH, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline (MCT) to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and PAK4 in the lung samples of PAH patients and paired healthy samples from the healthy subjects, in PHA cells and rats were detected by qRT-PCR. The pathological features of lung tissues were determined using HE staining. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, migration were detected by MTT, flow cytometry and wound healing assays, respectively. The protein expressions of PAK4, PCNA, P21, p-AKT and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in PAH, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia induction promoted cell proliferation, migration and apoptosis resistance accompanied with increased the expressions of PCNA and p-AKT/AKT and decreased that of P21 in PASMCs. MCT treatment increased p-AKT/AKT and decreased P21 expression, and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT and increased P21 levels via downregulating PAK4 in MCT-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregualting PAK4.
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