Heart RNA Decay

BACKGROUND: Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodeling. OBJECTIVE: The small conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. METHODS: Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months...

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. Up to 40% of cases are associated with heterozygous mutations in myosin binding protein C (cMyBP-C, MYBPC3). Most of these mutations lead to premature termination codons (PTC) and patients show reduction of functional cMyBP-C. This so-called haploinsufficiency most likely contributes to disease development. We analyzed mechanisms underlying haploinsufficiency using cardiac tissue from HCM-patients with truncation mutations in MYBPC3 (MYBPC3trunc )...

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8 , which encodes an essential TDMD factor...

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8 , which encodes an essential TDMD factor...

Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart...

BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. OBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. METHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers...

BACKGROUND: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3 , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. METHODS: We generated the knock-in mice ( Mylk3 +/fs and Mylk 3fs/fs ) with a familial dilated cardiomyopathy-associated MYLK3 frameshift mutation ( MYLK3 +/fs ) that had been identified previously by us (c...

AIMS: The activation of cardiac fibroblasts (CFs) leads to overproduction of collagens and subsequently cardiac fibrosis. However, the regulatory mechanism of CF function in the process of cardiac fibrosis remains unclear. This work investigated the function of polypyrimidine tract binding protein 1 (PTBP1)/nuclear receptor NR4A1 (Nur77)/fatty acid-binding protein 5 (FABP5) axis in myocardial fibrosis. METHODS AND RESULTS: Cardiac fibrosis was induced in mice suffered left anterior descending ligation...

Approximately 10% of monogenic diseases are caused by nonsense point mutations that generate premature termination codons (PTCs), resulting in a truncated protein and nonsense-mediated decay of the mutant mRNAs. Here, we demonstrate a mini-dCas13X-mediated RNA adenine base editing (mxABE) strategy to treat nonsense mutation-related monogenic diseases via A-to-G editing in a genetically humanized mouse model of Duchenne muscular dystrophy (DMD). Initially, we identified a nonsense point mutation (c.4174C>T, p...

Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20-40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used a combination of NGS, human-induced pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and nanopore long-read sequencing to identify the causal variant in a multi-generational pedigree of DCM. A four-generation family with familial DCM was investigated...

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current therapies and known causes of familial hypercholesterolemia. We found that cold shock domain-containing protein E1 (CSDE1) enhanced hepatic LDLR messenger RNA (mRNA) decay via its 3' untranslated region and regulated atherogenic lipoproteins in vivo...

Background and Objective: The recent emergence of epitranscriptomics provides an avenue for identifying RNA modifications implicated in the pathophysiology of human disease. To date, over 170 RNA modifications have been identified; these modifications are important because they can affect the fate of RNAs, including their decay, maturation, splicing, stability, and translational efficiency. Although RNA modifications have been reported in many tissues and disease contexts, detailed functional studies in the heart and cardiovascular disease are only beginning to be reported...

Staufen 1 (STAU1) is an RNA-binding protein that is essential in untransformed cells. In cancer cells, it is rather STAU1 overexpression that impairs cell proliferation. In this paper, we show that a modest increase in STAU1 expression in cancer cells triggers apoptosis as early as 12 h post-transfection and impairs proliferation in non-apoptotic cells for several days. Interestingly, a mutation that mimics the phosphorylation of STAU1 serine 20 is sufficient to cause these phenotypes, indicating that serine 20 is at the heart of the molecular mechanism leading to apoptosis...

Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent...

Viral diseases are a major threat to modern society and the global health system. It is therefore of utter relevance to understand the way viruses affect the host as a basis to find new treatment solutions. The understanding of viral myocarditis (VMC) is incomplete and effective treatment options are lacking. This review will discuss the mechanism, effects, and treatment options of the most frequent myocarditis-causing viruses namely enteroviruses such as Coxsackievirus B3 (CVB3) and Parvovirus B19 (PVB19) on the human heart...

Tritium is a water-soluble hydrogen isotope that releases beta rays during decay. In nature, tritium primarily exists as tritiated water (HTO), and its main source is nuclear power/processing plants. In recent decades, with the development of nuclear power industry, it is necessary to evaluate the impact of tritium on organisms. In this study, fertilized zebrafish embryos are treated with different HTO concentrations (3.7 × 103 Bq/ml, 3.7 × 104 Bq/ml, 3.7 × 105 Bq/ml). After treatment with HTO, the zebrafish embryos developed without evident morphological changes...

Purpose: This study aims to identify genetic lesions in patients with congenital heart disease (CHD) with or without other phenotypes. In this study, over 400 patients were recruited and several novel variants in known causative genes were identified. A Chinese patient clinically diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) was included in the study cohort. Methods: Targeted, whole exome, and Sanger sequencing were performed to identify genetic lesions...

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive heart condition which causes fibro-fatty myocardial scarring, ventricular arrhythmias, and sudden cardiac death. Most cases of ARVC can be linked to pathogenic mutations in the cardiac desmosome, but the pathophysiology is not well understood, particularly in early phases when arrhythmias can develop prior to structural changes. Here, we created a novel human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of ARVC from a patient with a c...

N6-methyladenosine (m6 A) is the most abundant and prevalent epigenetic modification of mRNA in mammals. This dynamic modification is regulated by m6 A methyltransferases and demethylases, which control the fate of target mRNAs through influencing splicing, translation and decay. Recent studies suggest that m6 A modification plays an important role in the progress of cardiac remodeling and cardiomyocyte contractile function. However, the exact roles of m6 A in cardiovascular diseases (CVDs) have not been fully explained...

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations...