Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be ...effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocytes are identified based on incorporation of
N-thymidine by multi-isotope imaging mass spectrometry (MIMS) and on being mononucleate/diploid. Furthermore, we demonstrate that exercise after myocardial infarction induces a robust cardiomyogenic response in an extended border zone of the infarcted area. Inhibition of miR-222, a microRNA increased by exercise in both animal models and humans, completely blocks the cardiomyogenic exercise response. These findings demonstrate that cardiomyogenesis can be activated by exercise in the normal and injured adult mouse heart and suggest that stimulation of endogenous cardiomyocyte generation could contribute to the benefits of exercise.
The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in ...end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist.
We constructed genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation (H3K36me3) enrichment for cardiomyopathic and normal human hearts. More than 506 Mb sequences per library were generated by high-throughput sequencing, allowing us to assign methylation scores to ≈28 million CG dinucleotides in the human genome. DNA methylation was significantly different in promoter CpG islands, intragenic CpG islands, gene bodies, and H3K36me3-enriched regions of the genome. DNA methylation differences were present in promoters of upregulated genes but not downregulated genes. H3K36me3 enrichment itself was also significantly different in coding regions of the genome. Specifically, abundance of RNA transcripts encoded by the DUX4 locus correlated to differential DNA methylation and H3K36me3 enrichment. In vitro, Dux gene expression was responsive to a specific inhibitor of DNA methyltransferase, and Dux siRNA knockdown led to reduced cell viability.
Distinct epigenomic patterns exist in important DNA elements of the cardiac genome in human end-stage cardiomyopathy. The epigenome may control the expression of local or distal genes with critical functions in myocardial stress response. If epigenomic patterns track with disease progression, assays for the epigenome may be useful for assessing prognosis in heart failure. Further studies are needed to determine whether and how the epigenome contributes to the development of cardiomyopathy.
Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle ...growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties.
Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8.
These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.
Stimulation of the nitric oxide (NO)--soluble guanylate (sGC)--protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing ...post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduces infarct size but also whether it protects against the development of post-MI heart failure.
Mice were subjected to 30 min ischaemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and (18)F-FDG-positron emission tomography (PET) were performed to determine infarct size. In the riociguat-treated mice, the resulting infarct size was smaller (8.5 ± 2.5% of total LV mass vs. 21.8% ± 1.7%. in controls, p = 0.005) and LV systolic function analysed by MRI was better preserved (60.1% ± 3.4% of preischaemic vs. 44.2% ± 3.1% in controls, p = 0.005). After 28 days, LV systolic function by echocardiography treated group was still better preserved (63.5% ± 3.2% vs. 48.2% ± 2.2% in control, p = 0.004).
Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size and better long-term preservation of LV systolic function. These findings suggest that sGC stimulation during reperfusion therapy may be a powerful therapeutic treatment strategy for preventing post-MI heart failure.
Hepatocyte nuclear factor 1 alpha (HNF1A), hepatocyte nuclear factor 4 alpha (HNF4A), and forkhead box protein A2 (FOXA2) are key transcription factors that regulate a complex gene network in the ...liver, creating a regulatory transcriptional loop. The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes. Our in silico analysis of HNF1A, HNF4A, and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrichment of these transcription factors specifically in the liver. Our previous studies identified HNF1A as a master regulator of fucosylation, glycan branching, and galactosylation of plasma glycoproteins. Here, we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype. We used the state-of-the-art clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) molecular tool for the downregulation of the HNF1A, HNF4A, and FOXA2 genes in HepG2 cells—a human liver cancer cell line. The results show that the downregulation of all three genes individually and in pairs affects the transcriptional activity of many glyco-genes, although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures. The effect is better seen as an overall change in the total HepG2 N-glycome, primarily due to the extension of biantennary glycans. We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure. We also propose a model showing feedback loops with the mutual activation of HNF1A–FOXA2 and HNF4A–FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
Rapidly advancing high-throughput sequencing technology is now bringing attention to many basic biological aspects of the human genome. DNA methylation refers to the epigenetic modification of ...cytosine nucleotides by a methyl group that occurs throughout the genome. Owing to its significant influence on protein-–DNA interactions and subsequent gene-expression control, some scientists call methylated-cytosines '‘the 5th nucleotide ’. We recently reported the first evidence of differential DNA methylation in human heart failure. Altered DNA methylation and a change in the expression of proximal genes have also been demonstrated in atherosclerotic plaques. For other diseases such as psychosis and cancer, the role of DNA methylation on disease pathogenesis and progression has already been shown and forms the target for new drug therapy. Understanding this aspect of disease biology may therefore contribute to the heart failure drug discovery pipeline. In this article, we summarize the basic biology of DNA methylation and discuss its implications in complex diseases such as heart failure.
The in vivo microenvironment of tissues provides myriad unique signals to cells. Thus, following isolation, many cell types change in culture, often preserving some but not all of their in vivo ...characteristics in culture. At least some of the in vivo microenvironment may be mimicked by providing specific cues to cultured cells. Here, we show that after isolation and during maintenance in culture, adherent rat islets reduce expression of key β-cell transcription factors necessary for β-cell function and that soluble pancreatic decellularized matrix (DCM) can enhance β-cell gene expression. Following chromatographic fractionation of pancreatic DCM, we performed proteomics to identify soluble factors that can maintain β-cell stability and function. We identified Apolipoprotein E (ApoE) as an extracellular protein that significantly increased the expression of key β-cell genes. The ApoE effect on beta cells was mediated at least in part through the JAK/STAT signaling pathway. Together, these results reveal a role for ApoE as an extracellular factor that can maintain the mature β-cell gene expression profile.
Hyperinsulinemia is a condition with extremely high levels of insulin in the blood. Various factors can lead to hyperinsulinemia in children and adolescents. Puberty is a period of significant change ...in children and adolescents. They do not have to have explicit symptoms for prediabetes, and certain health indicators may indicate a risk of developing this problem. The scientific study is designed as a cross-sectional study. In total, 674 children and adolescents of school age from 12 to 17 years old participated in the research. They received a recommendation from a pediatrician to do an OGTT (Oral Glucose Tolerance test) with insulinemia at a regular systematic examination. In addition to factor analysis, the study of the influence of individual factors was tested using RBF (Radial Basis Function) and SVM (Support Vector Machine) algorithm. The obtained results indicated statistically significant differences in the values of the monitored variables between the experimental and control groups. The obtained results showed that the number of adolescents at risk is increasing, and, in the presented research, it was 17.4%. Factor analysis and verification of the SVM algorithm changed the percentage of each risk factor. In addition, unlike previous research, three groups of children and adolescents at low, medium, and high risk were identified. The degree of risk can be of great diagnostic value for adopting corrective measures to prevent this problem and developing potential complications, primarily type 2 diabetes mellitus, cardiovascular disease, and other mass non-communicable diseases. The SVM algorithm is expected to determine the most accurate and reliable influence of risk factors. Using factor analysis and verification using the SVM algorithm, they significantly indicate an accurate, precise, and timely identification of children and adolescents at risk of hyperinsulinemia, which is of great importance for improving their health potential, and the health of society as a whole.
Henoch-Schönlein purpura (HSP) is a small blood vessel vasculitis, which usually manifests during childhood. The exact cause of the disease is unknown.
We reported a 14-year-old girl who had been ...admitted to our clinic due to the appearance of red macules on her extremities and face, vomiting, and pain in the abdomen and joints. The patient was initially diagnosed with Henoch-Schönlein purpura. At the end of the fourth week of illness, larvae of Strongyloides stercoralis were detected in stool samples. The patient was therefore treated with mebendazole, after which all symptoms permanently withdrew. About a month later laboratory examinations were repeated demonstrating increasing signs of renal damage. Kidney biopsy was performed, showing mesangioproliferative glomerulonephritis with crescents and IgA and C3 positive staining in the mesangium. Upon reviewing the clinical presentation, biochemically demonstrated progressive renal damage and biopsy results, the patient was diagnosed with HSP nephritis.
The time course of the disease and present knowledge concerning the pathogenic mechanisms of HSP suggest that Strongyloides stercoralis infection could have caused HSP in the presented patient, which was complicated by nephritis.
Molecular mechanisms of heart regeneration Vujic, Ana; Natarajan, Niranjana; Lee, Richard T.
Seminars in cell & developmental biology,
04/2020, Letnik:
100
Journal Article
Recenzirano
Odprti dostop
The adult mammalian heart is incapable of clinically relevant regeneration. The regenerative deficit in adult mammalian heart contrasts with the fetal and neonatal heart, which demonstrate ...substantial regenerative capacity after injury. This deficiency in adult mammals is attributable to the lack of resident stem cells after birth, combined with an inability of pre-existing cardiomyocytes to complete cytokinesis. Studies of neonatal heart regeneration in mammals suggest that latent regenerative potential can be re-activated. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation is key to stimulating true regeneration in adult humans. Here, we review recent advances in our understanding of cardiomyocyte proliferation that suggest molecular approaches to heart regeneration.
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