scholarly journals Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

2020 ◽  
Vol 21 (17) ◽  
pp. 6320
Author(s):  
Shanshan Gao ◽  
Deepa Puthenvedu ◽  
Raffaella Lombardi ◽  
Suet Nee Chen
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Autoimmune Response ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cellular Mechanisms ◽  
Paracrine Factors ◽  
Epicardial Cells ◽  
Genes Encoding ◽  
Advanced Stages ◽  
Canonical Wnt

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

scholarly journals Single Cell RNA-Sequencing Uncovers Paracrine Functions of the Epicardial-Derived Cells in Arrhythmogenic Cardiomyopathy

Circulation ◽  
2021 ◽  
Author(s):  
Ping Yuan ◽  
Sirisha M. Cheedipudi ◽  
Leila Rouhi ◽  
Siyang Fan ◽  
Lukas Simon ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cardiac Myocytes ◽  
Cardiac Dysfunction ◽  
Arrhythmogenic Cardiomyopathy ◽  
Paracrine Factors ◽  
Epicardial Cells ◽  
Single Cell Rna Sequencing ◽  
Genes Encoding

Background: Arrhythmogenic cardiomyopathy (ACM) manifests with sudden death, arrhythmias, heart failure, apoptosis, and myocardial fibro-adipogenesis. The phenotype typically starts at the epicardium and advances transmurally. Mutations in genes encoding desmosome proteins, including DSP (desmoplakin), are major causes of ACM. Methods: To delineate contributions of the epicardium to the pathogenesis of ACM, the Dsp allele was conditionally deleted in the epicardial cells in mice upon expression of tamoxifen-inducible Cre from the Wt1 locus. Wild type (WT) and Wt1-Cre ERT2 :Dsp W/F were crossed to Rosa26 mT/mG (R26 mT/mG ) dual reporter mice to tag the epicardial-derived cells (EDCs) with the EGFP reporter protein. Tagged EDCs from adult Wt1-Cre ERT2 :R26 mT/mG and Wt1-Cre ERT2 : R26 mT/mG : Dsp W/F mouse hearts were isolated by FACS and sequenced by single cell RNA-sequencing (scRNA-Seq). Results: WT1 expression was progressively restricted postnatally and was exclusive to the epicardium by postnatal day 21. Expression of Dsp was reduced in the epicardial cells but not in cardiac myocytes in the Wt1-Cre ERT2 :Dsp W/F mice. The Wt1-Cre ERT2 :Dsp W/F mice exhibited premature death, cardiac dysfunction, arrhythmias, myocardial fibro-adipogenesis, and apoptosis. ScRNA-Seq of ~ 18,000 EGFP-tagged EDCs identified genotype-independent clusters of endothelial cells (ECs), fibroblasts, epithelial cells, and a very small cluster of cardiac myocytes, which were confirmed upon co-immunofluorescence staining of the myocardial sections. Differentially expressed genes (DEGs) between the paired clusters in the two genotypes predicted activation of the inflammatory and mitotic pathways, including the TGFβ1 and fibroblast growth factors (FGFs), in the epicardial-derived fibroblast and epithelial clusters but their suppression in the EC cluster. The findings were corroborated by analysis of gene expression in the pooled RNA-Seq data, which identified predominant dysregulation of genes involved in epithelial-mesenchymal transition (EMT), and dysregulation of 146 genes encoding the secreted proteins (secretome), including genes in the TGFβ1 pathway. Activation of the TGFβ1 and its co-localization with fibrosis in the Wt1-Cre ERT2 :R26 mT/mG : Dsp W/F mouse heart was validated by complementary methods. Conclusions: Epicardial-derived cardiac fibroblasts and epithelial cells express paracrine factors, including TGFβ1 and FGFs, which mediate EMT, and contribute to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of ACM. The findings uncover contributions of the EDCs to the pathogenesis of ACM.

scholarly journals Exercise restores dysregulated gene expression in a mouse model of arrhythmogenic cardiomyopathy

2019 ◽  
Vol 116 (6) ◽  
pp. 1199-1213 ◽  
Author(s):  
Sirisha M Cheedipudi ◽  
Jinzhu Hu ◽  
Siyang Fan ◽  
Ping Yuan ◽  
Jennifer Karmouch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Treadmill Exercise ◽  
Arrhythmogenic Cardiomyopathy ◽  
Transcript Levels ◽  
Myocardial Apoptosis ◽  
Genes Encoding ◽  
Canonical Wnt

Abstract Aims Arrhythmogenic cardiomyopathy (ACM) is a myocardial disease caused mainly by mutations in genes encoding desmosome proteins ACM patients present with ventricular arrhythmias, cardiac dysfunction, sudden cardiac death, and a subset with fibro-fatty infiltration of the right ventricle predominantly. Endurance exercise is thought to exacerbate cardiac dysfunction and arrhythmias in ACM. The objective was to determine the effects of treadmill exercise on cardiac phenotype, including myocyte gene expression in myocyte-specific desmoplakin (Dsp) haplo-insufficient (Myh6-Cre:DspW/F) mice. Methods and results Three months old sex-matched wild-type (WT) and Myh6-Cre:DspW/F mice with normal cardiac function, as assessed by echocardiography, were randomized to regular activity or 60 min of daily treadmill exercise (5.5 kJ work per run). Cardiac myocyte gene expression, cardiac function, arrhythmias, and myocardial histology, including apoptosis, were analysed prior to and after 3 months of routine activity or treadmill exercise. Fifty-seven and 781 genes were differentially expressed in 3- and 6-month-old Myh6-Cre:DspW/F cardiac myocytes, compared to the corresponding WT myocytes, respectively. Genes encoding secreted proteins (secretome), including inhibitors of the canonical WNT pathway, were among the most up-regulated genes. The differentially expressed genes (DEGs) predicted activation of epithelial–mesenchymal transition (EMT) and inflammation, and suppression of oxidative phosphorylation pathways in the Myh6-Cre:DspW/F myocytes. Treadmill exercise restored transcript levels of two-third (492/781) of the DEGs and the corresponding dysregulated transcriptional and biological pathways, including EMT, inflammation, and secreted inhibitors of the canonical WNT. The changes were associated with reduced myocardial apoptosis and eccentric cardiac hypertrophy without changes in cardiac function. Conclusion Treadmill exercise restored transcript levels of the majority of dysregulated genes in cardiac myocytes, reduced myocardial apoptosis, and induced eccentric cardiac hypertrophy without affecting cardiac dysfunction in a mouse model of ACM. The findings suggest that treadmill exercise has potential beneficial effects in a subset of cardiac phenotypes in ACM.

Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology

2003 ◽  
Vol 285 (4) ◽  
pp. R709-R714 ◽  
Author(s):  
Friedrich C. Luft ◽  
Okan Toka ◽  
Hakan R. Toka ◽  
Jens Jordan ◽  
Sylvia Bähring
Keyword(s):  
Essential Hypertension ◽  
Molecular Mechanisms ◽  
Antihypertensive Drugs ◽  
Molecular Genetic ◽  
Plasma Renin ◽  
Salt Sensitivity ◽  
Ventrolateral Medulla ◽  
Sulfonylurea Receptor ◽  
Genetic Syndrome ◽  
Genes Encoding

Mendelian forms of hypertension have delivered a treasure trove of novel genes. To date, the molecular mechanisms of five such syndromes have been largely clarified, including glucocorticoid-remediable aldosteronism, Liddle's syndrome, apparent mineralocorticoid excess, an activating mutation of the mineralocorticoid receptor, and pseudohypoaldosteronism type 2. Each of these conditions features salt sensitivity with increased sodium and volume reabsorption by the kidney and low plasma renin activity. None of the gene loci for these syndromes has been convincingly linked to hypertension in the general population. We are investigating kindreds who have autosomal-dominant hypertension and brachydactyly. Affected persons invariably have both anomalies. The hypertension is severe and results in death at about age 50 years from stroke. The condition resembles essential hypertension, because renin, aldosterone, and norepinephrine responses are normal and no salt sensitivity is present. The response to antihypertensive drugs is general. Another feature is diminished baroreflex sensitivity with markedly impaired blood pressure buffering. Furthermore, the ventrolateral medulla may be compromised in these patients, because neurovascular anomalies are a regular finding. We mapped the gene(s) for this disease to chromosome 12p and narrowed the chromosomal region by studying more affected families. Interestingly, the same locus was recently mapped in Chinese families with essential hypertension. Our 3-centimorgan region contains genes encoding a phosphodiesterase, an ATP-dependent potassium channel, and its regulator the sulfonylurea receptor 2. Screening of the coding regions revealed that none of these candidate genes harbor obvious mutations; however, other genetic mechanisms may nevertheless compromise their function. Our study underscores the importance of regulatory physiology to the understanding of a complex genetic syndrome.

scholarly journals Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes

2016 ◽  
Vol 5 (2) ◽  
pp. 90 ◽  
Author(s):  
Deniz Akdis ◽  
Corinna Brunckhorst ◽  
Firat Duru ◽  
Ardan M Saguner ◽  
◽  
...  
Keyword(s):  
Heart Failure ◽  
Molecular Mechanisms ◽  
Task Force ◽  
Sudden Cardiac Arrest ◽  
Clinical Manifestations ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Implantable Cardioverter Defibrillators ◽  
Arrhythmogenic Cardiomyopathy ◽  
Genes Encoding

This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes. At later stages, heart failure may occur. Diagnosis is established with the 2010 Task Force Criteria (TFC). Modern imaging tools are crucial for ACM diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting functional and structural alternations. Of note, structural findings often become visible after electrical alterations, such as premature ventricular beats, ventricular fibrillation (VF) and ventricular tachycardia (VT). 12-lead ECG is important to assess for depolarisation and repolarisation abnormalities, including T-wave inversions as the most common ECG abnormality. Family history and the detection of causative mutations, mostly affecting the desmosome, have been incorporated in the TFC, and stress the importance of cascade family screening. Differential diagnoses include idiopathic right ventricular outflow tract (RVOT) VT, sarcoidosis, congenital heart disease, myocarditis, dilated cardiomyopathy, athlete’s heart, Brugada syndrome and RV infarction. Therapeutic strategies include restriction from endurance and competitive sports, β-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverter-defibrillators and endocardial/epicardial catheter ablation.

scholarly journals Genome-Wide Profiling of the Microrna Transcriptome Regulatory Network to Identify Putative Candidate Genes Associated with Backfat Deposition in Pigs

Animals ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 313 ◽  
Author(s):  
Xin Liu ◽  
Jianfei Gong ◽  
Ligang Wang ◽  
Xinhua Hou ◽  
Hongmei Gao ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Subcutaneous Fat ◽  
Fat Deposition ◽  
Backfat Thickness ◽  
Feed Conversion ◽  
Protein Coding ◽  
Genes Encoding

Backfat deposition is strongly related to carcass traits, growth rate, feed conversion rate, and reproductive performance in pig production. To understand the molecular mechanisms underlying porcine backfat thickness phenotypes, transcriptome and miRNA profiling of backfat from high-backfat thickness and low-backfat thickness pigs were performed by RNA sequencing. Twenty genes encoding for miRNAs and 126 genes encoding for protein-coding genes were found to be differentially expressed between the two libraries. After integrative analysis of DEMs targets and DEGs, a total of 33 mRNA‒miRNA interaction pairs were identified, and the regulatory networks of these pairs were determined. Among these genes, five (AQP9, DKK3, GLYCTK, GLIPR1, and DUSP2) related to fat deposition were found to be strong candidate genes, and mir-31-5p/AQP9 and mir-31-5p/GLIPR1 may play important roles in fat deposition. Additionally, potential adipogenesis-related genes and miRNAs were identified. These findings improve the current understanding of the molecular genetic mechanisms of subcutaneous fat deposition in pigs and provide a foundation for further studies.

scholarly journals The Molecular Mechanisms Associated with Aerobic Exercise-Induced Cardiac Regeneration

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 19
Author(s):  
Bing Bo ◽  
Yang Zhou ◽  
Qingyun Zheng ◽  
Guandong Wang ◽  
Ke Zhou ◽  
...  
Keyword(s):  
Aerobic Exercise ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Cardiac Regeneration ◽  
Cell Loss ◽  
Myocardial Cell ◽  
Cellular Mechanisms ◽  
Paracrine Factors ◽  
Ability To Regenerate ◽  
Exercise Induced

The leading cause of heart failure is cardiomyopathy and damage to the cardiomyocytes. Adult mammalian cardiomyocytes have the ability to regenerate, but this cannot wholly compensate for myocardial cell loss after myocardial injury. Studies have shown that exercise has a regulatory role in the activation and promotion of regeneration of healthy and injured adult cardiomyocytes. However, current research on the effects of aerobic exercise in myocardial regeneration is not comprehensive. This review discusses the relationships between aerobic exercise and the regeneration of cardiomyocytes with respect to complex molecular and cellular mechanisms, paracrine factors, transcriptional factors, signaling pathways, and microRNAs that induce cardiac regeneration. The topics discussed herein provide a knowledge base for physical activity-induced cardiomyocyte regeneration, in which exercise enhances overall heart function and improves the efficacy of cardiac rehabilitation.

scholarly journals Pathogenesis, Diagnosis and Risk Stratification in Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 11 (4) ◽  
pp. 263-289
Author(s):  
Maria Teresa Florio ◽  
Filomena Boccia ◽  
Erica Vetrano ◽  
Marco Borrelli ◽  
Thomas Gossios ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Molecular Mechanisms ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Electrical Instability ◽  
Genes Encoding ◽  
Nosological Entity ◽  
Clinical Tools ◽  
The Right

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease associated with sudden cardiac death (SCD). It is most frequently caused by mutations in genes encoding desmosomal proteins. However, there is growing evidence that ACM is not exclusively a desmosome disease but rather appears to be a disease of the connexoma. Fibroadipose replacement of the right ventricle (RV) had long been the hallmark of ACM, although biventricular involvement or predominant involvement of the left ventricle (LD-ACM) is increasingly found, raising the challenge of differential diagnosis with arrhythmogenic dilated cardiomyopathy (a-DCM). A-DCM, ACM, and LD-ACM are increasingly acknowledged as a single nosological entity, the hallmark of which is electrical instability. Our aim was to analyze the complex molecular mechanisms underlying arrhythmogenic cardiomyopathies, outlining the role of inflammation and autoimmunity in disease pathophysiology. Secondly, we present the clinical tools used in the clinical diagnosis of ACM. Focusing on the challenge of defining the risk of sudden death in this clinical setting, we present available risk stratification strategies. Lastly, we summarize the role of genetics and imaging in risk stratification, guiding through the appropriate patient selection for ICD implantation.

scholarly journals Molecular genetic mechanisms of sugar transport in plants in the absence and during arbuscular mycoryza development

2019 ◽  
Vol 17 (1) ◽  
pp. 81-99 ◽  
Author(s):  
Andrey P. Yurkov ◽  
Alexey A. Kryukov ◽  
Anastasia O. Gorbunova ◽  
Alexei M. Afonin ◽  
Anastasija A. Kirpichnikova ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Sugar Transport ◽  
Carbon Assimilation ◽  
Plant Cells ◽  
Am Fungi ◽  
Root Cells ◽  
Expression Of Genes ◽  
Carbohydrate Transport ◽  
Genes Encoding

The review is aimed to analyze molecular mechanisms of carbohydrate transport during the formation of arbuscular mycorrhiza (AM), a widespread symbiosis of plants with Glomeromycotina subdivision fungi. Due to AM-symbiosis, plants receive microelements, mainly phosphorus, and fungi are supplied by products of carbon assimilation. The study of sugar transport mechanisms in plants as well as between plants and symbiont is methodologically difficult because of the obligatory status of AM fungi. The mechanisms of carbohydrate transport in leaf and root cells are concerned, particular interest is paid to transporters, specific to AM structures. Several resumptive schemes are designed. SWEET family of transporters (Sugars Will Eventually be Exported Transporters), including AM-specific uniporters are reviewed. We summarize results on expression of genes encoding transporter in cells of plants without AM, in AM-plant cells with arbuscules and AM-plant cells without arbuscules. The data on genes of MST proteins family (Monosaccharide Transporters) participating in direct transport of sugars from the soil to the foliar mycelium of AM fungi are considered.

Molecular Basis and Clinical Aspects of Hereditary Megakaryocyte and Platelet Membrane Glycoprotein Disorders

1996 ◽  
Vol 16 (02) ◽  
pp. 114-138 ◽  
Author(s):  
R. E. Scharf
Keyword(s):  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Platelet Membrane ◽  
Clinical Aspects ◽  
Membrane Glycoprotein ◽  
Membrane Glycoproteins ◽  
Membrane Expression ◽  
Receptor Complexes ◽  
Platelet Membrane Glycoprotein

SummarySpecific membrane glycoproteins (GP) expressed by the megakaryocyte-platelet system, including GPIa-lla, GPIb-V-IX, GPIIb-llla, and GPIV are involved in mediat-ing platelet adhesion to the subendothelial matrix. Among these glycoproteins, GPIIb-llla plays a pivotal role since platelet aggregation is exclusively mediated by this receptor and its interaction with soluble macromolecular proteins. Inherited defects of the GPIIb-llla or GPIb-V-IX receptor complexes are associated with bleeding disorders, known as Glanzmann's thrombasthenia, Bernard-Soulier syndrome, or platelet-type von Willebrand's disease, respectively. Using immuno-chemical and molecular biology techniques, rapid advances in our understanding of the molecular genetic basis of these disorders have been made during the last few years. Moreover, analyses of patients with congenital platelet membrane glycoprotein abnormalities have provided valuable insights into molecular mechanisms that are required for structural and functional integrity, normal biosynthesis of the glycoprotein complexes and coordinated membrane expression of their constituents. The present article reviews the current state of knowledge of the major membrane glycoproteins in health and disease. The spectrum of clinical bleeding manifestations and established diagnostic criteria for each of these dis-orders are summarized. In particular, the variety of molecular defects that have been identified so far and their genetic basis will be discussed.

Natural Products for Regulating Macrophages M2 Polarization

2020 ◽  
Vol 15 (7) ◽  
pp. 559-569 ◽  
Author(s):  
Zhen Chang ◽  
Youhan Wang ◽  
Chang Liu ◽  
Wanli Smith ◽  
Lingbo Kong
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Research Progress ◽  
Cellular Mechanisms ◽  
Pharmacological Activities ◽  
Current Review ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

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