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1.
PLoS One ; 15(8): e0237731, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813752

RESUMO

Sudden cardiac death (SCD) is an important cause of mortality worldwide. It accounts for approximately half of all deaths from cardiovascular disease. While coronary artery disease and acute myocardial infarction account for the majority of SCD in the elderly population, inherited cardiac diseases (inherited CDs) comprise a substantial proportion of younger SCD victims with a significant genetic component. Currently, the use of next-generation sequencing enables the rapid analysis to investigate relationships between genetic variants and inherited CDs causing SCD. Genetic contribution to risk has been considered an alternate predictor of SCD. In the past years, large numbers of SCD susceptibility variants were reported, but these results are scattered in numerous publications. Here, we present the SCD-associated Variants Annotation Database (SVAD) to facilitate the interpretation of variants and to meet the needs of data integration. SVAD contains data from a broad screening of scientific literature. It was constructed to provide a comprehensive collection of genetic variants along with integrated information regarding their effects. At present, SVAD has accumulated 2,292 entries within 1,239 variants by manually surveying pertinent literature, and approximately one-third of the collected variants are pathogenic/likely-pathogenic following the ACMG guidelines. To the best of our knowledge, SVAD is the most comprehensive database that can provide integrated information on the associated variants in various types of inherited CDs. SVAD represents a valuable source of variant information based on scientific literature and benefits clinicians and researchers, and it is now available on http://svad.mbc.nctu.edu.tw/.


Assuntos
Bases de Dados Genéticas/estatística & dados numéricos , Morte Súbita Cardíaca/etiologia , Cardiopatias/genética , Modelos Genéticos , Simulação por Computador , Morte Súbita Cardíaca/epidemiologia , Cardiopatias/mortalidade , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos
2.
Vet Clin North Am Equine Pract ; 36(2): 235-241, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534853

RESUMO

There have been some advances in understanding the genetic contribution to ventricular septal defects in Arabians, sudden death in racehorses, and atrial fibrillation in racehorses. No genetic analyses have been published for aortic rupture in Friesians or atrioventricular block in donkeys despite strong evidence for a genetic cause. To date, no genetic mutation has been identified for any equid cardiac disease. With the advancement of genetic tools and resources, we are moving closer to discoveries that may explain the heritable basis of inherited equid cardiac disease.


Assuntos
Testes Genéticos/veterinária , Cardiopatias/veterinária , Doenças dos Cavalos/genética , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/veterinária , Testes Genéticos/métodos , Cardiopatias/genética , Comunicação Interventricular/genética , Comunicação Interventricular/veterinária , Cavalos , Mutação
3.
J Cardiovasc Transl Res ; 13(3): 402-416, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253744

RESUMO

Cancer therapies have been evolving from conventional chemotherapeutics to targeted agents. This has fulfilled the hope of greater efficacy but unfortunately not of greater safety. In fact, a broad spectrum of toxicities can be seen with targeted therapies, including cardiovascular toxicities. Among these, cardiomyopathy and heart failure have received greatest attention, given their profound implications for continuation of cancer therapies and cardiovascular morbidity and mortality. Prediction of risk has always posed a challenge and even more so with the newer targeted agents. The merits of accurate risk prediction, however, are very evident, e.g. facilitating treatment decisions even before the first dose is given. This is important for agents with a long half-life and high potential to induced life-threatening cardiac complications, such as myocarditis with immune checkpoint inhibitors. An opportunity to address these needs in the field of cardio-oncology is provided by the expanding repertoire of "-omics" and other tools in precision medicine and their integration in a systems biology approach. This may allow for new insights into patho-mechanisms and the creation of more precise and cost-effective risk prediction tools with the ultimate goals of improved therapy decisions and prevention of cardiovascular complications. Herein, we explore this topic as a future approach to translating the complexity of cardio-oncology to the reality of patient care.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Sobreviventes de Câncer , Cardiologia , Cardiopatias/induzido quimicamente , Oncologia , Neoplasias/tratamento farmacológico , Medicina de Precisão , Inibidores de Proteínas Quinases/efeitos adversos , Biologia de Sistemas , Animais , Cardiotoxicidade , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/imunologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Medição de Risco , Fatores de Risco
4.
BMC Cardiovasc Disord ; 20(1): 43, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013934

RESUMO

BACKGROUND: The current diagnostic methods and treatments still fail to lower the incidence of anthracycline-induced cardiotoxicity effectively. In this study, we aimed to (1) analyze the cardiotoxicity-related genes after breast cancer chemotherapy in gene expression database and (2) carry out bioinformatic analysis to identify cardiotoxicity-related abnormal expressions, the biomarkers of such abnormal expressions, and the key regulatory pathways after breast cancer chemotherapy. METHODS: Cardiotoxicity-related gene expression data (GSE40447) after breast cancer chemotherapy was acquired from the Gene Expression Omnibus (GEO) database. The biomarker expression data of women with chemotherapy-induced cardiotoxicity (group A), chemotherapy history but no cardiotoxicity (group B), and confirmatory diagnosis of breast cancer but normal ejection fraction before chemotherapy (group C) were analyzed to obtain the mRNA with differential expressions and predict the micro RNAs (miRNAs) regulating the differential expressions. The miRanda formula and functional enrichment analysis were used to screen abnormal miRNAs. Then, the Gene Ontology (GO) analysis was adapted to further screen the miRNAs related to cardiotoxicity after breast cancer chemotherapy. RESULT: The data of differential analysis of biomarker expression of groups A, B, and C using the GSE40447-related gene expression profile database showed that there were 30 intersection genes. The differentially expressed mRNAs were predicted using the miRanda and Target Scan software, and a total of 2978 miRNAs were obtained by taking the intersections. Further, the GO analysis and targeted regulatory relationship between miRNA and target genes were used to establish miRNA-gene interaction network to screen and obtain seven cardiotoxicity-related miRNAs with relatively high centrality, including hsa-miR-4638-3p, hsa-miR-5096, hsa-miR-4763-5p, hsa-miR-1273 g-3p, hsa-miR6192, hsa-miR-4726-5p and hsa-miR-1273a. Among them, hsa-miR-4638-3p and hsa-miR-1273 g-3p had the highest centrality. The PCR verification results were consistent with those of the chip data. There are differentially expressed miRNAs in the peripheral blood of breast cancer patients with anthracycline cardiotoxicity. Among them, hsa-miR-4638-3p and hsa-miR-1273 g-3p are closely associated with the onset of anthracycline cardiotoxicity in patients with breast cancer. The signaling pathway is mainly concentrated in TGF-ß signaling pathway and adhesion signaling pathway. CONCLUSIONS: Changes in expression of hsa-miR-4638-3p and hsa-miR-1273 g-3p may contribute to the detection of anthracyclines induced cardiac toxicity, and their potential function may be related to TGF-ß signaling pathway and adhesion signaling pathway.


Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , MicroRNA Circulante/sangue , Biologia Computacional , Perfilação da Expressão Gênica , Cardiopatias/sangue , Adulto , Idoso , Cardiotoxicidade , MicroRNA Circulante/genética , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico , Cardiopatias/genética , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Fatores de Risco , Transdução de Sinais/genética
5.
Proc Natl Acad Sci U S A ; 117(6): 3053-3062, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31980526

RESUMO

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.


Assuntos
Diagnóstico por Imagem , Metabolômica , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Genótipo , Cardiopatias/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
6.
Toxicol Lett ; 318: 1-11, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618665

RESUMO

Triptolide (TP), a principal bioactive component extracted from traditional Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted wide attention of its therapeutic effects on inflammation and autoimmune diseases. However, the therapeutic application of TP is hindered by severe cardiomyocyte toxicity and narrow therapeutic window. We previously identified that the p53 was an indispensable contributor in TP-induced myocardial injury. p53 has an inhibitory effect on IKKß-NF-κB pathway that regulates glucose transporters (GLUT) expression. Based on these evidences, we speculate that p53 mediates TP-disturbed glucose uptake by blocking IKKß-NF-κB signaling. This study focused on the effect of TP on cardiac glucose uptake and the role of p53 in glucose metabolism in cardiomyocytes, and p53 -/- mice. TP treatment depressed glucose consumption and ATP production resulting in myocardial damage. Incubation with ATP (5 mM) remarkably decreased the cellular damage. Immunoblotting and immunofluorescence identified that TP suppressed glucose uptake by restricting IKKß-NF-κB signaling activation, GLUT1 and GLUT4 expression. p53 inhibition alleviated the cell damage and the compromise of glucose uptake. Mechanistically, p53 antagonist PFTα abolished TP-induced the inhibition of IKKß, IκBα phosphorylation, p65 nuclear translocation, and GLUT1, GLUT4 expression. Consistently, in acute heart injury models, p53 deficiency upregulated IKKß-NF-κB activation and GLUT1, GLUT4 protein levels which was also indicated as amelioration of heart histological injury after 1.2 mg kg-1 TP administration. The present findings indicate that TP-induced p53 overactivation suppresses glucose uptake by inhibiting IKKß-NF-κB pathway and downregulating NF-κB-dependent GLUT1 and GLUT4 expression.


Assuntos
Diterpenos/toxicidade , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Quinase I-kappa B/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Fenantrenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Compostos de Epóxi/toxicidade , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
7.
J Ethnopharmacol ; 246: 112210, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31479707

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Danshen tablet, an herbal preparation consisting of salviae miltiorrhizae, notoginseng and borneolum, is extensively employed clinically to treat angina pectoris, coronary arteriosclerosis and significantly improve microcirculation. AIM OF THE STUDY: To reveal the potential underlying cardioprotective mechanism(s) in isoproterenol-induced myocardial injury in high-fat-diet fed mice. MATERIALS AND METHODS: Cardiac transcriptomics was analyzed by Illumina mRNA-Seq sequencing. The restored cardiovascular diseases (CVD)-related genes by Compound Danshen tablet were validated by quantitative real time polymerase chain reaction (qRT-PCR). Furthermore, Cardiac metabolomics were also performed using gas chromatography-mass spectrometry. RESULTS: From the transcriptomics study, we found the levels of 24 up-regulated and 44 down-regulated genes in the control compared to model groups. Among them, seven gene levels were restored by treatment of Compound Danshen tablet. Four CVD-related genes at the mRNA level (Sprr1a, Ppp1r3c, Bmp10 and Hspa1b) were validated successfully by qRT-PCR. From the metabolomics study, 37 differentially expressed metabolites were identified between the control and model groups. Among them, 21 metabolites were restored by treatment of Compound Danshen tablet. These altered metabolites are involved in glucose metabolism, fatty acid metabolism and amino acid metabolism. CONCLUSION: These genes and metabolites might provide clues for further molecular mechanistic study of Compound Danshen tablet.


Assuntos
Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Cardiopatias/genética , Cardiopatias/metabolismo , Animais , Dieta Hiperlipídica , Perfilação da Expressão Gênica , Cardiopatias/induzido quimicamente , Cardiopatias/tratamento farmacológico , Isoproterenol , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Comprimidos , Transcriptoma/efeitos dos fármacos
9.
Acta Biochim Pol ; 66(4): 483-489, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31834688

RESUMO

Nowadays, mesenchymal stem cells (MSCs) are essential players in cellular therapy and regenerative medicine. MSCs are used to treat cardiac disorders by intramyocardial injection or injection into the bloodstream. Therefore, a premise of successful MSC-based therapy is that the cells reach the site of injury and home the damaged tissue. In response to inflammatory conditions, MSCs can potentially move into the place of injury and colonize damaged tissues, where they participate in their regeneration. This review presents the current knowledge of the mechanisms of MSCs migration and target tissue homing in the field of cardiovascular therapies.


Assuntos
Cardiopatias/terapia , Coração/crescimento & desenvolvimento , Transplante de Células-Tronco Mesenquimais , Medicina Regenerativa/tendências , Diferenciação Celular/genética , Movimento Celular/genética , Coração/fisiopatologia , Cardiopatias/genética , Humanos , Células-Tronco Mesenquimais/citologia
11.
Genomics Proteomics Bioinformatics ; 17(5): 540-545, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31765830

RESUMO

Next-generation sequencing (NGS) technologies generate thousands to millions of genetic variants per sample. Identification of potential disease-causal variants is labor intensive as it relies on filtering using various annotation metrics and consideration of multiple pathogenicity prediction scores. We have developed VPOT (variant prioritization ordering tool), a python-based command line tool that allows researchers to create a single fully customizable pathogenicity ranking score from any number of annotation values, each with a user-defined weighting. The use of VPOT can be informative when analyzing entire cohorts, as variants in a cohort can be prioritized. VPOT also provides additional functions to allow variant filtering based on a candidate gene list or by affected status in a family pedigree. VPOT outperforms similar tools in terms of efficacy, flexibility, scalability, and computational performance. VPOT is freely available for public use at GitHub (https://github.com/VCCRI/VPOT/). Documentation for installation along with a user tutorial, a default parameter file, and test data are provided.


Assuntos
Interface Usuário-Computador , 3-Hidroxiantranilato 3,4-Dioxigenase/genética , Algoritmos , Bases de Dados Genéticas , Cardiopatias/congênito , Cardiopatias/genética , Humanos , Polimorfismo Genético , Sequenciamento Completo do Exoma
12.
Ideggyogy Sz ; 72(9-10): 325-336, 2019 Sep 30.
Artigo em Húngaro | MEDLINE | ID: mdl-31625699

RESUMO

With the acceptance of "The developmental origins of health and disease" concept in the 1990s, it became clear that epigenetic inheritance, which do not involve changes in the DNA sequence has important role in the pathogenesis of diseases. Epigenetic regulation serves the adaptation to the changing environment and maintains the reproductive fitness even on the drawback of increased risk of diseases in later life. The role of epigenetic mechanisms in chronic non-communicable diseases has been well established. Recent studies have revealed that epigenetic changes have also causal role in certain pediatric diseases. The review evaluates the recent epigenetic findings in the pathomechanism of common pediatric diseases. The wide range and long-lasting duration of epigenetic regulations give importance to the subject. Methods are already available to evaluate a part of the epigenetic changes in the clinical practice, presently aiming primarily the estimation of the disease risk or definition of diagnosis. Furthermore, there are already available limited means to influence the epigenetic regulation.


Assuntos
Metilação de DNA/fisiologia , Epigênese Genética , Cardiopatias , Infecções , Transtornos Mentais , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Cardiopatias/genética , Humanos , Infecções/genética , Transtornos Mentais/genética , Doenças Metabólicas/genética , Pediatria , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
13.
Int J Mol Sci ; 20(20)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658614

RESUMO

Heart failure is associated with profound alterations of energy metabolism thought to play a major role in the progression of this syndrome. SIRT1 is a metabolic sensor of cellular energy and exerts essential functions on energy metabolism, oxidative stress response, apoptosis, or aging. Importantly, SIRT1 deacetylates the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), the master regulator of energy metabolism involved in mitochondrial biogenesis and fatty acid utilization. However, the exact role of SIRT1 in controlling cardiac energy metabolism is still incompletely understood and conflicting results have been obtained. We generated a cardio-specific inducible model of Sirt1 gene deletion in mice (Sirt1ciKO) to decipher the role of SIRT1 in control conditions and following cardiac stress induced by pressure overload. SIRT1 deficiency induced a progressive cardiac dysfunction, without overt alteration in mitochondrial content or properties. Sixteen weeks after Sirt1 deletion an increase in mitochondrial reactive oxygen species (ROS) production and a higher rate of oxidative damage were observed, suggesting disruption of the ROS production/detoxification balance. Following pressure overload, cardiac dysfunction and alteration in mitochondrial properties were exacerbated in Sirt1ciKO mice. Overall the results demonstrate that SIRT1 plays a cardioprotective role on cardiac energy metabolism and thereby on cardiac function.


Assuntos
Cardiopatias/genética , Coração , Pressão , Sirtuína 1/genética , Sirtuína 1/metabolismo , Animais , Ecocardiografia , Fibrose/patologia , Deleção de Genes , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Miócitos Cardíacos , Estresse Oxidativo , Espécies Reativas de Oxigênio , Tamoxifeno/efeitos adversos
14.
Biol Pharm Bull ; 42(12): 2045-2053, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31597885

RESUMO

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Trastuzumab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes erbB-2 , Loci Gênicos/genética , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Trastuzumab/farmacologia
15.
PLoS Genet ; 15(10): e1008354, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589606

RESUMO

Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple polymorphic genes. One gene confirmed to influence this parameter is the cardiomyocyte-specific kinase Tnni3k. Here, we have studied Tnni3k alleles across a number of species. Using a newly-generated kinase-dead allele in mice, we show that Tnni3k function is dependent on its kinase activity. In an in vitro kinase assay, we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. We show that two kinase domain frameshift mutations in mice cause loss-of-function consequences by nonsense-mediated decay. We further show that the Tnni3k gene in two species of mole-rat has independently devolved into a pseudogene, presumably associated with the transition of these species to a low metabolism and hypoxic subterranean life. This may be explained by the observation that Tnni3k function in mice converges with oxidative stress to regulate mononuclear diploid cardiomyocyte frequency. Unlike other studied rodents, naked mole-rats have a surprisingly high (30%) mononuclear cardiomyocyte level but most of their mononuclear cardiomyocytes are polyploid; their mononuclear diploid cardiomyocyte level (7%) is within the known range (2-10%) of inbred mouse strains. Naked mole-rats provide further insight on a recent proposal that cardiomyocyte polyploidy is associated with evolutionary acquisition of endothermy.


Assuntos
Evolução Molecular , Cardiopatias/genética , Proteínas Serina-Treonina Quinases/genética , Alelos , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Cardiopatias/metabolismo , Ventrículos do Coração/crescimento & desenvolvimento , Ventrículos do Coração/metabolismo , Humanos , Mutação com Perda de Função/genética , Camundongos , Ratos-Toupeira/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/genética , Poliploidia , Regeneração/genética
17.
Nat Commun ; 10(1): 4457, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575858

RESUMO

Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.


Assuntos
Trifosfato de Adenosina/metabolismo , Canalopatias/metabolismo , Predisposição Genética para Doença/genética , Deficiência Intelectual/metabolismo , Doenças Musculares/metabolismo , Mutação , Receptores Sulfonilureia/genética , Receptores Sulfonilureia/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Linhagem Celular , Criança , Modelos Animais de Doenças , Facies , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Coração , Cardiopatias/genética , Cardiopatias/metabolismo , Homozigoto , Humanos , Hipertricose/genética , Hipertricose/metabolismo , Deficiência Intelectual/parasitologia , Masculino , Complexo Mediador/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Doenças Musculares/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Linhagem , Fenótipo , Rubídio , Sequenciamento Completo do Genoma , Adulto Jovem , Peixe-Zebra
18.
Biogerontology ; 20(6): 741-761, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31473864

RESUMO

Aging is a progressive decline of physiological function in tissue and organ accompanying both accumulation of DNA damage and reduction of non-coding DNA. Peripheral non-coding DNA/heterochromatin has been proposed to protect the genome and centrally-located protein-coding sequences in soma and male germ cells against radiation and the invasion of exogenous nucleic acids. Therefore, this review summarizes the reduction of non-coding DNA/heterochromatin (including telomeric DNA and rDNA) and DNA damage accumulation during normal physiological aging and in various aging-related diseases. Based on analysis of data, it is found that DNA damage accumulation is roughly negatively correlated with the reduction of non-coding DNA and therefore speculated that DNA damage accumulation is likely due to the reduction of non-coding DNA protection in genome defense during aging. Therefore, it is proposed here that means to increase the total amount of non-coding DNA and/or heterochromatin prior to the onset of these diseases could potentially better protect the genome and protein-coding DNA, reduce the incidence of aging-related diseases, and thus lead to better health during aging.


Assuntos
Envelhecimento/genética , Dano ao DNA , DNA/genética , Cardiopatias/genética , Heterocromatina/genética , Humanos , Neoplasias/genética , Telômero
19.
Amyloid ; 26(4): 234-242, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31502881

RESUMO

Background: Hereditary transthyretin (TTR) related amyloidosis (ATTRv) is a life-threatening condition, which can potentially affect all organs. The objective was to identify the hearing status of patients with cardiac ATTRv and describe their audiological pattern. Methods: Nineteen patients with confirmed diagnosis of ATTRv cardiac amyloidosis (CA) underwent otoscopy and audiological tests, including pure tone and speech audiometry. Results: 74% were male, with a mean age of 72 ± 1.8 years. The main mutations were Val122Ile (n = 7) and Val30Met (n = 6). Objective hearing loss was detected in 17 patients (89%), whereas only 37% complained of hearing loss. ATTRv patients presented a different audiometric profile compared to patients of the same age with presbycusis: a higher prevalence and worse hearing thresholds compared to age-related expectations (ISO). Hearing loss affected all frequencies with, unexpectedly, mixed or conductive hearing loss (35%). According to the type of mutation, there was an increased rate of sensorineural or mixed/conductive hearing loss. Conclusions: the present study indicates that hearing loss is more prevalent and worse in patients with ATTRv amyloidosis than in the general population, while mostly clinically under-estimated. It suggests that ATTRv deposits could infiltrate the various anatomical structures of the inner and mild ear.


Assuntos
Neuropatias Amiloides Familiares/complicações , Perda Auditiva/complicações , Cardiopatias/complicações , Neuropatias Amiloides Familiares/genética , Feminino , Perda Auditiva/genética , Cardiopatias/genética , Humanos , Masculino , Estudos Prospectivos
20.
Biofactors ; 45(6): 844-856, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31418958

RESUMO

Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well-organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post-transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA-based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy-related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.


Assuntos
Apoptose/genética , Autofagia/genética , MicroRNAs/genética , Aterosclerose/genética , Regulação da Expressão Gênica/genética , Cardiopatias/genética , Humanos , Neoplasias/genética , Fenótipo , Transdução de Sinais/genética , Tuberculose/genética , Viroses/genética
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