Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation.
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ABSTRACT:
SUBMITTER: Kunzel SR
PROVIDER: S-EPMC8487716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR-146b-5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR-146b-5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR-146b-5p transfection in human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs)-fibroblast co-culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR-146b-5p downregulation on atrial fibrosis. The expression level of miR-146b-5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR-146b-5p transfection in hiPSC-aCMs-fibroblast co-culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR-146b-5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR-146b-5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR-146b-5p overexpressed co-culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR-146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR-146b-5p might become an effective therapeutic approach for preventing atrial fibrosis.
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Project description:Background Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosome is a promising cell-free therapeutic approach for the treatment of AF. The purpose of this study was to explore the mechanisms underlying exosomes derived from atrial myocytes regulated atrial remodeling and ask whether their manipulation allows for therapeutic modulation of fibrosis potential abnormalities during AF. Methods We isolated exosomes from atrial myocytes and patients serum, microRNA (miRNA) sequencing analyzed the exosomal miRNAs in atrial myocytes-exosomes and patients serum-exosomes. mRNA sequencing and bioinformatics analysis corroborate the key gene as direct targets of miR-210-3p. Results The miRNAs sequencing analysis identified that miR-210-3p expression significantly increased in exosomes of tachypacing atrial myocytes and serum of AF patients. In vitro, the analysis showed that miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, KO miR-210-3p could reduce the incidence of AF and ameliorate atrial fibrosis induced by Ang Ⅱ. The mRNA sequencing analysis and Dual-Luciferase reporter assay proved that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is the potential target gene of miR-210-3p. The functional analysis suggests that GPD1L regulated atrial fibrosis via PI3K/AKT signaling pathway. Besides, silencing GPD1L in atrial fibroblasts induced cells proliferation and these effects could be reversed by PI3K inhibitor (LY294002). Conclusion We demonstrate that atrial myocytes-derived exosomal miR-210-3p promoted the proliferation and collagen synthesis via inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be as a novel target to improve atrial fibrosis in AF.
2022-08-17 | GSE210894 | GEO
Project description:Scn1b-/- mice are a model of Early Infantile Developmental Epileptic Encephalopathy (EIDEE). These mice exhibit characteristic seen in patients such as spontaneous siezures, ataxia, growth abnormalites, and a high incidence of premature mortality. The goal of this study was to identify changes in gene expression between Scn1b wild-type and Scn1b-/- mice in the atria
2020-06-17 | GSE152617 | GEO
Project description:BACKGROUND:Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. METHODS AND RESULTS:We sequenced a ?158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. CONCLUSIONS:We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.
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Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia characterized by rapid and multiple irregular excitations within the atria. AF is associated with serious morbidity and increased mortality, and its prevalence is prospected to increase as society ages. The limited therapeutic efficacy of AF treatment as well as its high socioeconomic burden makes AF a major clinical challenge. Despite our expanding knowledge of individual proteins and pathways involved in the complex pathophysiology of atrial fibrillation (AF), an unbiased overview of proteins and functionally enriched biological processes as well as their crosstalk is lacking. Here, we performed an explorative proteomics analysis to reveal the global abundance of proteins in cardiac tissue of patients, and deciphered functionally grouped gene ontologies (GO) to uncover a perspective of the disease biology driving or driven by AF. A total of 2703 proteins were identified by liquid chromatography coupled to tandem mass spectrometry. Among them, 150 proteins (accounting for 5.6% of 2703) had a significantly altered abundance (100 proteins increased and 50 decreased) in AF. A significant biological connection was found between those (protein-protein interaction enrichment p-value=1.0e-16). GO enrichment analysis showed that these 150 proteins were mainly located in extracellular/cytoplasmic vesicles, mitochondrion, and cytoskeletal compartments. Correspondingly, the 100 proteins increased in AF were significantly enriched in the GO terms related to immune system, metabolic process, iron process, ECM disassembly, mitochondrial translation and apoptotic signaling. Partially clustered proteins with dense functional link were found in immune system and metabolic process, and were respectively annotated in neutrophil degranulation, and oxoacid metabolic process coupled to the subunits of mitochondrial dehydrogenase NADH. Those processes enriched in AF had crosstalk via the proteins involved in neutrophil degranulation. Selected proteins such as LCN2 (neutrophil degranulation), CA3 (immune system), NDUFS2 (complex I) and MYH10 (actin motor protein) were validated by western blot or qPCR in an independent cohort. The 50 proteins decreased in AF were collectively enriched in vesicle-mediated transport and actin filament-based movement. We demonstrate that important biological processes underlying persistent AF as well as their crosstalk via the components of neutrophil degranulation. Our study provides a novel insight for a more efficient targeting strategy for AF treatment.
2021-09-08 | PXD013230 | Pride
Project description:Tongguan capsule is a compound Chinese medicine used to treat ischaemic heart diseases. This study aimed to investigate whether Tongguan capsule-derived herb (TGD) has a preventive effect on atrial fibrillation (AF) in post-myocardial infarction (MI) rats and to determine the underlying mechanisms. MI was induced by ligation of the left anterior descending coronary artery. TGD was administered to the post-MI rats over a 4-week period. The TGD-treated rats had lower rates of AF inducibility and shorter AF durations than the MI rats. TGD improved the left atrial (LA) conduction velocity and homogeneity. It reduced the fibrosis-positive areas and the protein levels of collagen types I and III in the left atrium. In vitro, it inhibited the expression of collagen types I and III by inhibiting the proliferation, migration, differentiation and cytokine secretion of cardiac fibroblasts (CFs). In conclusion, the current study demonstrated that TGD reduces susceptibility to AF and improves LA conduction function in rats with post-MI by inhibiting left atrial fibrosis and modulating CFs. Targeting the CF population may be a novel antiarrhythmic therapeutic approach.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2020-07-10 | GSE148507 | GEO
Project description:Atrial fibrillation (AFib) and the risk of its lethal complications are worsened by atrial fibrosis. A recent study implicates osteopontin (encoded by Spp1) secreted by atrial TREM2+ macrophages in this fibrosis. Here, we show that silencing Spp1 in TREM2+ cardiac macrophages using an antibody-siRNA conjugate (ARC) reduces atrial fibrosis and suppresses AFib, thus offering a new immunotherapy for this common arrhythmia.
2024-09-12 | GSE272503 | GEO
Project description:AF is the most common arrhythmia in clinical practice. In addition to the severe effect on quality of life, patients with AF are at higher risk of stroke and mortality. Recent studies have suggested that atrial and ventricular substrate play a major role in the development and maintenance of AF. Cardiac MRI has emerged as a viable tool for interrogating the underlying substrate in AF patients. Its advantage includes localisation and quantification of structural remodelling. Cardiac MRI of the atrial substrate is not only a tool for management and treatment of arrhythmia, but also to individualise the prevention of stroke and major cardiovascular events. This article provides an overview of atrial imaging using cardiac MRI and its clinical implications in the AF population.
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Project description:Atrial fibrillation (AF) rat models and rat cardiac fibroblasts (CFs) with overexpressed or inhibited miR-10a were used to investigate the possible role of miR-10a-mediated transforming growth factor-? (TGF-?1)/Smads signaling in cardiac fibrosis and fibroblast proliferation in rats with AF. Gene ontology and pathway enrichment analyses were used to identify the possible function of miR-10a in cardiac fibrosis. The results showed that overexpressed miR-10a significantly prolonged the duration of AF, further elevated the collagen volume fraction (CVF), and increased the viability of CFs in AF rats; these findings were in contrast with the findings for rats with inhibition of miR-10a (all P<0.05). Moreover, miR-10a overexpression could promote miR-10a, collagen-I, collagen III, ?-SMA, and TGF-?1 protein expression and increase the levels of hydroxyproline but reduced Smad7 protein expression in atrial tissues and CFs in AF rats. Not surprisingly, inhibiting miR-10a led to completely contrasting results (all P<0.05). Moreover, TGF-?1 treatment could reverse the inhibitory effect of miR-10a down-regulation on cardiac fibrosis in CFs. Bioinformatics analysis and luciferase reporter assay results demonstrated that miR-10a bound directly to the 3'-UTR of BCL6, which is involved in cell growth and proliferation. Thus, our study indicate that down-regulation of miR-10a may inhibit collagen formation, reduce atrial structure remodeling, and decrease proliferation of CFs, eventually suppressing cardiac fibrosis in AF rats via inhibition of the TGF-?1/Smads signaling pathway.
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