Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

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The genetics of hypertrophic cardiomyopathy

Global Cardiology Science and Practice ◽

10.21542/gcsp.2018.36 ◽

2018 ◽

Vol 2018 (3) ◽

Cited By ~ 3

Author(s):

Mohammed Akhtar ◽

Perry Elliott

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Treatment Strategies ◽

Glycogen Storage ◽

Calcium Handling ◽

Clinical Role ◽

Genes Encoding ◽

Disease Stratification ◽

Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease. It is also used to diagnose genocopies, such as lysosomal and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification and offer potential targets for disease-modifying therapy in the near future.

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The Salivary miRNome: A Promising Biomarker of Disease

MicroRNA ◽

10.2174/2211536610666210412154455 ◽

2021 ◽

Vol 10 ◽

Author(s):

Sara Tomei ◽

Harshitha Shobha Manjunath ◽

Selvasankar Murugesan ◽

Souhaila Al Khodor

Keyword(s):

Current Knowledge ◽

Transcriptional Level ◽

Biological Processes ◽

Circulating Mirnas ◽

Disease Pathogenesis ◽

Technical Aspects ◽

Recent Developments ◽

Health And Disease ◽

Non Coding Rnas

: MicroRNAs (miRNAs) are non-coding RNAs ranging from 18-24 nucleotides also known to regulate the human genome mainly at the post-transcriptional level. MiRNAs were shown to play an important role in most biological processes such as apoptosis and in the pathogenesis of many diseases such as cardiovascular diseases and cancer. Recent developments of advanced molecular high-throughput technologies have enhanced our knowledge of miRNAs. MiRNAs can now be discovered, interrogated, and quantified in various body fluids, and hence can serve as diagnostic and therapeutic markers for many diseases. While most studies use blood as a sample source to measure circulating miRNAs as possible biomarkers for disease pathogenesis, fewer studies have assessed the role of salivary miRNAs in health and disease. This review aims at providing an overview of the current knowledge of the salivary miRNome, addressing the technical aspects of saliva sampling and highlighting the applicability of miRNA screening to clinical practice.

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Hypertrophic cardiomyopathy: genetics

ESC CardioMed ◽

10.1093/med/9780198784906.003.0350 ◽

2018 ◽

pp. 1443-1450

Author(s):

Mohammed Majid Akhtar ◽

Luis Rocha Lopes

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Mapk Pathway ◽

Glycogen Storage ◽

Cellular Level ◽

Causative Mutation ◽

Clinical Role ◽

Genes Encoding ◽

Associated Proteins

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

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Genetic and Epigenetic Aspects of Atopic Dermatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21186484 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6484 ◽

Cited By ~ 1

Author(s):

Bogusław Nedoszytko ◽

Edyta Reszka ◽

Danuta Gutowska-Owsiak ◽

Magdalena Trzeciak ◽

Magdalena Lange ◽

...

Keyword(s):

Atopic Dermatitis ◽

Treatment Strategies ◽

Structural Proteins ◽

Epigenetic Changes ◽

Epigenetic Alterations ◽

Adaptive Immune ◽

Genes Encoding ◽

Inflammatory Processes ◽

Non Coding Rnas

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.

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Long Non-Coding RNAs and Related Molecular Pathways in the Pathogenesis of Epilepsy

International Journal of Molecular Sciences ◽

10.3390/ijms20194898 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4898 ◽

Cited By ~ 5

Author(s):

Villa ◽

Lavitrano ◽

Combi

Keyword(s):

Biological Processes ◽

Complete Understanding ◽

Aberrant Expression ◽

Protein Coding ◽

Diagnostic Biomarkers ◽

Functional Roles ◽

The Central Nervous System ◽

Non Coding Rnas ◽

Underlying Mechanisms ◽

Coding Capacity

Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, apoptosis, and ion channels dysfunction, currently the pathogenesis of epilepsy is not yet completely understood. Long non-coding RNAs (lncRNAs), a class of long transcripts without protein-coding capacity, have emerged as regulatory molecules that are involved in a wide variety of biological processes. A growing number of studies reported that lncRNAs participate in the regulation of pathological processes of epilepsy and they are dysregulated during epileptogenesis. Moreover, an aberrant expression of lncRNAs linked to epilepsy has been observed both in patients and in animal models. In this review, we summarize latest advances concerning the mechanisms of action and the involvement of the most dysregulated lncRNAs in epilepsy. However, the functional roles of lncRNAs in the disease pathogenesis are still to be explored and we are only at the beginning. Additional studies are needed for the complete understanding of the underlying mechanisms and they would result in the use of lncRNAs as diagnostic biomarkers and novel therapeutic targets.

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Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms21020524 ◽

2020 ◽

Vol 21 (2) ◽

pp. 524 ◽

Cited By ~ 2

Author(s):

Marina R. Hadjicharalambous ◽

Mark A. Lindsay

Keyword(s):

Chronic Disease ◽

Epithelial Cell ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Activation ◽

Lung Fibroblast ◽

Biological Processes ◽

Aberrant Expression ◽

Non Coding Rnas

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disease characterized by excessing scarring of the lungs leading to irreversible decline in lung function. The aetiology and pathogenesis of the disease are still unclear, although lung fibroblast and epithelial cell activation, as well as the secretion of fibrotic and inflammatory mediators, have been strongly associated with the development and progression of IPF. Significantly, long non-coding RNAs (lncRNAs) are emerging as modulators of multiple biological processes, although their function and mechanism of action in IPF is poorly understood. LncRNAs have been shown to be important regulators of several diseases and their aberrant expression has been linked to the pathophysiology of fibrosis including IPF. This review will provide an overview of this emerging role of lncRNAs in the development of IPF.

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Emerging microRNA biomarkers for colorectal cancer diagnosis and prognosis

Open Biology ◽

10.1098/rsob.180212 ◽

2019 ◽

Vol 9 (1) ◽

pp. 180212 ◽

Cited By ~ 20

Author(s):

Bing Chen ◽

Zijing Xia ◽

Ya-Nan Deng ◽

Yanfang Yang ◽

Peng Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Target Genes ◽

Research Use ◽

Biological Processes ◽

Functional Roles ◽

Analytical Technique ◽

Diagnosis And Prognosis ◽

Recurrence Prediction ◽

Extracellular Mirnas ◽

Non Coding Rnas

MicroRNAs (miRNAs) are one abundant class of small, endogenous non-coding RNAs, which regulate various biological processes by inhibiting expression of target genes. miRNAs have important functional roles in carcinogenesis and development of colorectal cancer (CRC), and emerging evidence has indicated the feasibility of miRNAs as robust cancer biomarkers. This review summarizes the progress in miRNA-related research, including study of its oncogene or tumour-suppressor roles and the advantages of miRNA biomarkers for CRC diagnosis, treatment and recurrence prediction. Along with analytical technique improvements in miRNA research, use of the emerging extracellular miRNAs is feasible for CRC diagnosis and prognosis.

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EVLncRNAs 2.0: an updated database of manually curated functional long non-coding RNAs validated by low-throughput experiments

Nucleic Acids Research ◽

10.1093/nar/gkaa1076 ◽

2020 ◽

Vol 49 (D1) ◽

pp. D86-D91

Author(s):

Bailing Zhou ◽

Baohua Ji ◽

Kui Liu ◽

Guodong Hu ◽

Fei Wang ◽

...

Keyword(s):

Interaction Network ◽

Circular Rnas ◽

Biological Processes ◽

Drug Resistant ◽

Functional Roles ◽

Visual Interaction ◽

Disease Associations ◽

Non Coding Rnas ◽

Central Database ◽

Data Browsing

Abstract Long non-coding RNAs (lncRNAs) play important functional roles in many diverse biological processes. However, not all expressed lncRNAs are functional. Thus, it is necessary to manually collect all experimentally validated functional lncRNAs (EVlncRNA) with their sequences, structures, and functions annotated in a central database. The first release of such a database (EVLncRNAs) was made using the literature prior to 1 May 2016. Since then (till 15 May 2020), 19 245 articles related to lncRNAs have been published. In EVLncRNAs 2.0, these articles were manually examined for a major expansion of the data collected. Specifically, the number of annotated EVlncRNAs, associated diseases, lncRNA-disease associations, and interaction records were increased by 260%, 320%, 484% and 537%, respectively. Moreover, the database has added several new categories: 8 lncRNA structures, 33 exosomal lncRNAs, 188 circular RNAs, and 1079 drug-resistant, chemoresistant, and stress-resistant lncRNAs. All records have checked against known retraction and fake articles. This release also comes with a highly interactive visual interaction network that facilitates users to track the underlying relations among lncRNAs, miRNAs, proteins, genes and other functional elements. Furthermore, it provides links to four new bioinformatics tools with improved data browsing and searching functionality. EVLncRNAs 2.0 is freely available at https://www.sdklab-biophysics-dzu.net/EVLncRNAs2/.

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Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00913.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. H807-H815 ◽

Cited By ~ 29

Author(s):

David Barefield ◽

Mohit Kumar ◽

Pieter P. de Tombe ◽

Sakthivel Sadayappan

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Functional Impairments ◽

Tissue Samples ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Genes Encoding ◽

Heterozygous Carriers ◽

Sarcomere Proteins ◽

Whole Heart

The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C′-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ∼40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 μm (+/t 68.5 ± 4.1 mN/mm2 vs. +/+ 82.2 ± 3.2) and 2.3 μm (+/t 79.2 ± 3.1 mN/mm2 vs. +/+ 95.5 ± 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 ± 0.12 vs. +/+ 2.58 ± 0.43) and E′/A′ (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.

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lncRNA Gm16410 Mediates PM2.5-Induced Macrophage Activation via PI3K/AKT Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.618045 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jingbin Xu ◽

Henggui Xu ◽

Kexin Ma ◽

Yue Wang ◽

Ben Niu ◽

...

Keyword(s):

Lung Inflammation ◽

Macrophage Activation ◽

Biological Effects ◽

Pulmonary Inflammation ◽

Biological Processes ◽

Functional Roles ◽

Non Coding Rna ◽

Macrophage Polarity ◽

Insight Into

PM2.5 refers to atmospheric particulate matters with a diameter of less than 2.5 μm. The deposit of PM2.5 in lung cells can cause oxidative stress, leading to changes in macrophage polarity, which can subsequently cause pulmonary inflammation. Long-chain non-coding RNA (lncRNA) is a class of transcripts that regulate biological processes through multiple mechanisms. However, the role of lncRNA in PM2.5-induced lung inflammation has not been established. In this study, the biological effects and associated mechanism of lncRNA in PM2.5-induced change in macrophage polarity were investigated. The lncRNA-mediated PM2.5-induced macrophage inflammation and lung inflammation-associated injury were also determined. Mice were exposed to chronic levels of PM2.5, and changes in the expression of lncRNA in the lung were measured by lncRNA microarray. lncRNAs that showed significant changes in expression in response to PM2.5 were identified. lncRNA showing the biggest change was subjected to further analysis to determine its functional roles and mechanisms with respect to macrophage activation. The result showed that a significant reduction in expression of one lncRNA, identified as lncGm16410, was observed in the lung of mice and RAW264.7 cells following exposure to PM2.5. lncGm16410 suppressed PM2.5-induced macrophage activation via the SRC protein-mediated PI3K/AKT signaling pathway. PM2.5 promoted lung inflammation by downregulating the expression of lncGm16410, enhancing the activation of macrophages. Thus, lncGm16410 might provide new insight into the prevention of PM2.5 injury.

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