LncRNA MIAT impairs cardiac contractile function by acting on mitochondrial translocator protein TSPO in a mouse model of myocardial infarction.
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ABSTRACT:
SUBMITTER: Bai X
PROVIDER: S-EPMC8093248 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:TSPO is mainly expressed in the mitochondrial outer membrane of microglia in the central nervous system, and its expression is greatly increased when microglia are activated. However, the role and mechanism of this protein in microglial activation is not well characterized. In this study, we investigated the role of TSPO in microglial activation by isolating primary microglia from TSPO knockout mice and constructing TSPO-knockdown microglial cell line. We found that TSPO deficiency significantly inhibited microglial activation induced by LPS or IL-4. Mechanistically, TSPO deficiency greatly decreased the mitochondrial membrane potential and ATP production. Moreover, an analysis of cellular energy metabolism showed that TSPO deficiency suppressed mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in microglial overall metabolic deficits. Together, our results reveal a crucial role of TSPO in microglial activation through the regulation of mitochondrial metabolism, thus providing a potential therapeutic target for neuroinflammation-related diseases of the central nervous system.
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Project description:BACKGROUND:Coronary atherosclerotic disease (CAD) is one of the greatest causes of death and disability around the world, and has emerged as a major public health problem. Acute myocardial infarction (AMI) is the most serious type of CAD. Myocardial infarction (MI) association transcript (MIAT) has demonstrated that it plays an important role in AMI. PURPOSE:To investigate the association between MIAT promoter polymorphisms and AMI in Chinese Han population. METHODS:A total of 212 AMI patients and 218 healthy controls were recruited. The long non-coding RNA (lncRNA)-MIAT promoter polymorphisms (single nucleotide polymorphisms (SNPs)) were obtained using polymerase chain reaction (PCR) and sequencing techniques. Chi-square test was used to analyze the allele and genotype frequencies of each SNP in two groups. Logistic regression analysis was used to analyze the association of each SNP with AMI. Linkage disequilibrium (LD) and haplotype analysis were performed using SHEsis software. A JASPAR database search predicts transcription factors transition of linked polymorphism in MIAT promoter. RESULTS:Ten SNPs were found, including rs56371714, rs55892869, rs151057042, rs2157598, rs150465374, rs5761664, rs8142890, rs5752375, rs9608515 and rs1055293700, whereas rs1055293700 was found only in the control group. Single and logistic regression analysis showed that there was a significant correlation between rs5752375 and rs9608515 polymorphisms and AMI, while other sites had no relationship with AMI. These MI association polymorphisms may change the binding sites with transcription factor. CONCLUSIONS:The polymorphisms of lncRNA-MIAT promoter rs5752375 and rs9608515 were significantly associated with AMI in Chinese Han population. This result would be of clinical importance for the early diagnosis of AMI.
| S-EPMC7040461 | biostudies-literature
Project description:BACKGROUND Long non-coding RNA of myocardial infarction associated transcript (lncRNA-MIAT) has a reported role in microvascular dysfunction. This study aimed to investigate the role of lncRNA-MIAT and its effects on transforming growth factor-?1 (TGF-?1) signaling in patients with diabetic retinopathy and in ARPE-19 adult retinal pigment epithelial cells in vitro. MATERIAL AND METHODS Study participants provided plasma samples and included patients with non-proliferative diabetic retinopathy (n=52), patients with diabetes without diabetic retinopathy (n=63), and healthy controls (n=56). Plasma levels of lncRNA-MIAT and TGF-?1 were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Pearson correlation analysis was performed on the plasma data, and the diagnostic relevance of plasma levels of lncRNA-MIAT for diabetic retinopathy was evaluated by receiver operating characteristic (ROC) curve analysis. Cells of the human retinal pigment epithelial cell line, ARPE-19, were cultured in high glucose with construction and transfection of a MIAT expression plasmid vector. Viability of ARPE-19 cells was detected by the MTT assay and Western blot measured the expression levels of TGF-?1. RESULTS Plasma levels of lncRNA-MIAT were significantly increased in patients with diabetic retinopathy compared with patients with diabetes without diabetic retinopathy and with healthy controls. ARPE-19 cells cultured in a high glucose environment showed reduced cell viability and upregulation of lncRNA-MIAT expression. CONCLUSIONS Increased plasma levels of lncRNA-MIAT were significantly associated with the presence of diabetic retinopathy, and increased expression of lncRNA-MIAT reduced the viability of ARPE-19 cells in vitro by upregulating TGF-?1 signaling.
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Project description:BackgroundCatechin protects heart from myocardial ischaemia/reperfusion (MI/R) injury. However, whether catechin inhibits H/R-induced myocardial cell apoptosis is largely unknown.ObjectiveThis study aims to investigate the underlying mechanism of catechin in inhibiting the apoptosis of H/R-induced myocardial cells.MethodsLncRNA MIAT expression was detected by qRT-PCR. Cell viability of H9C2 cells was detected using CCK-8 assay. The apoptosis of H9C2 cells was detected by flow cytometry. The interaction between CREB and MIAT promoter regions was confirmed by dual-luciferase reporter gene assay and ChIP assay.ResultsIn MI/R rats, catechin improved heart function and down-regulated lncRNA MIAT expression in myocardial tissue. In H/R-induced H9C2 cells, catechin protected against cell apoptosis, and lncRNA MIAT overexpression attenuated this protective effect of catechin. We confirmed that transcription factor CREB could bind to MIAT promoter region, and catechin suppressed lncRNA MIAT expression through up-regulating CREB. Catechin improved mitochondrial function and relieved apoptosis through promoting Akt/Gsk-3β activation. In addition, MIAT inhibited Akt/Gsk-3β activation and promoted cell apoptosis in H/R-induced H9C2 cells. Finally, we found catechin promoted Akt/Gsk-3β activation through inhibiting MIAT expression in H/R-induced H9C2 cells.ConclusionCatechin relieved H/R-induced myocardial cell apoptosis through regulating CREB/lncRNA MIAT/Akt/Gsk-3β pathway.
| S-EPMC7011153 | biostudies-literature
Project description:Myocarditis is more severe in men than in women and difficult to diagnose due to a lack of imaging modalities that directly detect myocardial inflammation. Translocator protein 18 kDa (TSPO) is used extensively to image brain inflammation due to its presence in CD11b(+) brain microglia. In this study, we examined expression of TSPO and CD11b in mice with coxsackievirus B3 (CVB3) myocarditis and biopsy sections from myocarditis patients in order to determine if it could be used to image myocarditis. We found that male mice with CVB3 myocarditis upregulated more genes associated with TSPO activation than female mice. TSPO expression was increased in the heart of male mice and men with myocarditis compared with female subjects due to testosterone, where it was expressed predominantly in CD11b(+) immune cells. We show that TSPO ligands detect myocardial inflammation using microSPECT, with increased uptake of [(125)I]-IodoDPA-713 in male mice with CVB3 myocarditis compared with undiseased controls.
| S-EPMC3951973 | biostudies-literature
Project description:The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its non-selective cellular expression pattern implies roles beyond inflammatory processes. In the present study, we investigated whether neuronal activity modifies TSPO levels in the adult central nervous system. First, we used single-cell RNA sequencing to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, followed by confocal laser scanning microscopy to verify TSPO protein in neuronal and non-neuronal cell populations. We then quantified TSPO mRNA and protein levels after stimulating neuronal activity with distinct stimuli, including designer receptors exclusively activated by designer drugs (DREADDs), exposure to a novel environment and acute treatment with the psychostimulant drug, amphetamine. Single-cell RNA sequencing demonstrated a non-selective and multi-cellular gene expression pattern of TSPO at basal conditions in the adult mouse hippocampus. Confocal laser scanning microscopy confirmed that TSPO protein is present in neuronal and non-neuronal (astrocytes, microglia, vascular endothelial cells) cells of cortical (medial prefrontal cortex) and subcortical (hippocampus) brain regions. Stimulating neuronal activity through chemogenetic (DREADDs), physiological (novel environment exposure) or psychopharmacological (amphetamine treatment) approaches led to consistent increases in TSPO gene and protein levels in neurons, but not in microglia or astrocytes. Taken together, our findings show that neuronal activity has the potential to modify TSPO levels in the adult central nervous system. These findings challenge the general assumption that altered TSPO expression or binding unequivocally mirrors ongoing neuroinflammation and emphasize the need to consider non-inflammatory interpretations in some physiological or pathological contexts.
| S-EPMC8440208 | biostudies-literature
Project description:Prevention of infarct scar thinning and dilatation and stimulation of scar contracture can prevent progressive heart failure. Since microRNA 145 (miR-145) plays an important role in cardiac fibroblast response to wound healing and cardiac repair after an myocardial infarction (MI), using a miR-145 knock-out (KO) mouse model, we evaluated contribution of down-regulation of miR-145 to cardiac fibroblast and myofibroblast function during adverse cardiac remodelling. Cardiac function decreased more and the infarct size was larger in miR-145 KO than that in WT mice after MI and this phenomenon was accompanied by a decrease in cardiac fibroblast-to-myofibroblast differentiation. Quantification of collagen I and α-SMA protein levels as well as wound contraction revealed that transdifferentiation of cardiac fibroblasts into myofibroblasts was lower in KO than WT mice. In vitro restoration of miR-145 induced more differentiation of fibroblasts to myofibroblasts and this effect involved the target genes Klf4 and myocardin. MiR-145 contributes to infarct scar contraction in the heart and the absence of miR-145 contributes to dysfunction of cardiac fibroblast, resulting in greater infarct thinning and dilatation. Augmentation of miR-145 could be an attractive target to prevent adverse cardiac remodelling after MI by enhancing the phenotypic switch of cardiac fibroblasts to myofibroblasts.
| S-EPMC7417705 | biostudies-literature
Project description:Rationale: As a hallmark of various heart diseases, cardiac fibrosis ultimately leads to end-stage heart failure. Anti-fibrosis is a potential therapeutic strategy for heart failure. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of heart diseases that promise to serve as therapeutic targets. However, few lncRNAs have been directly implicated in cardiac fibrosis. Methods: The lncRNA expression profiles were assessed by microarray in cardiac fibrotic and remote ventricular tissues in mice with myocardial infarction. The mechanisms and functional significance of lncRNA-AK137033 in cardiac fibrosis were further investigated with both in vitro and in vivo models. Results: We identified 389 differentially expressed lncRNAs in cardiac fibrotic and remote ventricular tissues in mice with myocardial infarction. Among them, a lncRNA (AK137033) we named Safe was enriched in the nuclei of fibroblasts, and elevated in both myocardial infarction and TGF-?-induced cardiac fibrosis. Knockdown of Safe prevented TGF-?-induced fibroblast-myofibroblast transition, aberrant cell proliferation and secretion of extracellular matrix proteins in vitro, and mended the impaired cardiac function in mice suffering myocardial infarction. In vitro studies indicated that knockdown of Safe significantly inhibited the expression of its neighboring gene Sfrp2, and vice versa. The Sfrp2 overexpression obviously disturbed the regulatory effects of Safe shRNAs in both the in vitro cultured cardiac fibroblasts and myocardial infarction-induced fibrosis. Dual-Luciferase assay demonstrated that Safe and Sfrp2 mRNA stabilized each other via their complementary binding at the 3'-end. RNA electrophoretic mobility shift assay and RNA immunoprecipitation assay indicated that RNA binding protein HuR could bind to Safe-Sfrp2 RNA duplex, whereas the knockdown of HuR dramatically reduced the stabilization of Safe and Sfrp2 mRNAs, down-regulated their expression in cardiac fibroblasts, and thus inhibited TGF-?-induced fibrosis. The Safe overexpression partially restrained the phenotype change of cardiac fibroblasts induced by Sfrp2 shRNAs, but not that induced by HuR shRNAs. Conclusions: Our study identifies Safe as a critical regulator of cardiac fibrosis, and demonstrates Safe-Sfrp2-HuR complex-mediated Sfrp2 mRNA stability is the underlying mechanism of Safe-regulated cardiac fibrosis. Fibroblast-enriched Safe could represent a novel target for anti-fibrotic therapy in heart diseases.
| S-EPMC6831303 | biostudies-literature
Project description:Rationale: Most current cardiac regeneration approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to determine whether the lncRNA small nucleolar RNA host gene 1 Snhg1 (Snhg1) could form a positive feedback loop with c-Myc to induce cardiac regeneration. Methods: Quantitative PCR and in situ hybridization experiments were performed to determine the Snhg1 expression patterns in fetal and myocardial infarction (MI) hearts. Gain- and Loss-of-function assays were conducted to explore the effect of Snhg1 on cardiomyocyte (CM) proliferation and cardiac repair following MI. We further constructed CM-specific Snhg1 knockout mice to confirm the proliferative effect exerted by Snhg1 using CRISPR/Cas9 technology. RNA sequencing and RNA pulldown were performed to explore how Snhg1 mediated cardiac regeneration. Chromatin immunoprecipitation and luciferase reporter assays were used to demonstrate the positive feedback loop between Snhg1 and c-Myc. Results: Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Overexpression of Snhg1 promoted CM proliferation, angiogenesis, and inhibited CM apoptosis after myocardial infarction, which further improved post-MI cardiac function. Antagonism of Snhg1 in early postnatal mice inhibited CM proliferation and impaired cardiac repair after MI. Mechanistically, Snhg1 directly bound to phosphatase and tensin homolog (PTEN) and induced PTEN degradation, activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to promote CM proliferation. The c-Myc protein, one of downstream targets of PI3K/AKT signaling, functioned as a transcription factor by binding to the promoter regions of Snhg1. Perturbation of the positive feedback between Snhg1 and c-Myc by mutation of the binding sequence significantly affected Snhg1-induced CM proliferation. Conclusions: Snhg1 effectively elicited CM proliferation and improved cardiac function post-MI by forming a positive feedback loop with c-Myc to sustain PI3K/Akt signaling activation, and thus may be a promising cardiac regeneration strategy in treating heart failure post-MI.
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Project description:The 18-kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a transmembrane protein in the outer mitochondrial membrane. TSPO has long been described as being indispensable for mitochondrial cholesterol import that is essential for steroid hormone production. In contrast to this initial proposition, recent experiments reexamining TSPO function have demonstrated that it is not involved in steroidogenesis. This fundamental change has forced a reexamination of the functional interpretations made for TSPO that broadly impacts both basic and clinical research across multiple fields. In this minireview, we recapitulate the key studies from 25 years of TSPO research and concurrently examine their limitations that perhaps led towards the incorrect association of TSPO and steroid hormone production. Although this shift in understanding raises new questions regarding the molecular function of TSPO, these recent developments are poised to have a significant positive impact for research progress in steroid endocrinology.
| S-EPMC4399280 | biostudies-literature