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1.
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
2.
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 , Infecção , Transtornos Mentais , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Cardiopatias/genética , Humanos , Infecção/genética , Transtornos Mentais/genética , Doenças Metabólicas/genética , Pediatria , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
3.
Adv Exp Med Biol ; 1193: 155-174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368103

RESUMO

A major pathophysiological mechanism behind the development of diabetic heart diseases is oxidative stress mediated by toxic reactive aldehydes such as 4-hydroxynonenal (4HNE). Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that has been found to detoxify these deleterious aldehydes and thereby mitigate cardiac damage. Furthermore, its protective role in cellular signaling reverses aberrations caused by hyperglycemia, thereby protecting cardiac function. This chapter assesses the role of ALDH2 in diabetic heart diseases by examining preclinical studies where ALDH2 activity is perturbed in both decreased and increased directions. In doing so, issues in improving ALDH2 activity in select human populations are elucidated, and further research directions are discussed.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Diabetes Mellitus/genética , Cardiopatias/genética , Aldeídos/efeitos adversos , Cardiopatias/complicações , Humanos , Estresse Oxidativo
4.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(2): 214-218, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31309761

RESUMO

Pathological processes such as myocardial apoptosis, cardiac hypertrophy, myocardial fibrosis, and cardiac electrical remodeling are involved in the development and progression of most cardiac diseases. MicroRNA-21 (miR-21) has been found to play an important role in heart diseases as a novel type of endogenous regulators, which can inhibit cardiomyocyte apoptosis, improve hypertension and cardiac hypertrophy, promote myocardial fibrosis and atrial electrical remodeling. In this review, we summarize the research progress on the function of miR-21 in heart diseases and its mechanism, and discuss its potential application in diagnosis and treatment of heart diseases.


Assuntos
Cardiopatias , MicroRNAs , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Cardiopatias/genética , Cardiopatias/fisiopatologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/patologia
5.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
6.
Life Sci ; 228: 121-127, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039364

RESUMO

AIMS: B1- and B2-kinin receptors play a major role in several cardiovascular diseases. Therefore, we aimed to evaluate cardiac functional consequences of B1- and B2-kinin receptors ablation, focusing on the cardiac ROS and NO generation. MAIN METHODS: Cardiac contractility, ROS, and NO generation, and protein expression were evaluated in male wild-type (WT), B1- (B1-/-) and B2-kinin (B2-/-) knockout mice. KEY FINDINGS: Impaired contractility in B1-/- and B2-/- hearts was associated with oxidative stress through upregulation of NADPH oxidase p22phox subunit. B1-/- and B2-/- hearts presented higher NO and peroxynitrite levels than WT. Despite decreased sarcoplasmic reticulum Ca2+ ATPase pump (SERCA2) expression, nitration at tyrosine residues of SERCA2 was markedly higher in B1-/- and B2-/- hearts. SIGNIFICANCE: B1- and B2-kinin receptors govern ROS generation, while disruption of B1- and B2-kinin receptors leads to impaired cardiac dysfunction through excessive tyrosine nitration on the SERCA2 structure.


Assuntos
Cardiopatias/genética , Coração/fisiopatologia , Receptor B1 da Bradicinina/genética , Receptor B2 da Bradicinina/genética , Animais , Deleção de Genes , Cardiopatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Miocárdica , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo
7.
Medicine (Baltimore) ; 98(15): e15065, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985656

RESUMO

Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.


Assuntos
5'-Nucleotidase/genética , Calcinose/genética , Variação Genética , Cardiopatias/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Proteínas Ligadas por GPI/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores Sexuais , Suécia , Rigidez Vascular/genética
8.
Life Sci ; 224: 12-22, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30872181

RESUMO

AIMS: MicroRNAs (miRNAs or miRs) are a large class of small noncoding RNAs. The present study aims to evaluate the effect of miR-451 on cardiac remodeling in diabetic cardiomyopathy. MAIN METHODS: Mice were injected with streptozotocin (STZ) to induce diabetes. Twelve weeks after final STZ injection, mice were subjected to myocardial injection of adenovirus (Ad)-shmiR-451 to knock down miR-451. Mouse heart endothelial cells (MHECs) were treated with a miR-451 antagomir to inhibit miR451 and were exposed to high glucose. KEY FINDINGS: Sixteen weeks after STZ injection, mice exhibited no significant cardiac hypertrophy but did exhibit serious cardiac fibrosis. MiR-451 knockdown attenuated cardiac fibrosis and improved cardiac function. Moreover, we found that miR-451 knockdown suppressed endothelial-to-mesenchymal transition (EndMT) in diabetic mouse hearts. Hyperglycemia-induced EndMT in MHECs was attenuated by the miR-451 antagomir. Activation of AMPKa1/mTOR was decreased in diabetic mouse heart tissue and hyperglycemia-stimulated MHECs, which was increased following miR-451 knockdown or inhibition. AMPKa1 siRNA abrogated the anti-EndMT effects of miR-451 knockdown in MHECs. SIGNIFICANCE: miR-451 participates in the pathology of diabetic cardiomyopathy via AMPKa1-regulated EndMT in endothelial cells.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Fibrose/terapia , Cardiopatias/terapia , MicroRNAs/antagonistas & inibidores , Substâncias Protetoras , RNA Interferente Pequeno/genética , Animais , Animais Recém-Nascidos , Fibrose/etiologia , Fibrose/genética , Cardiopatias/etiologia , Cardiopatias/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
9.
Biomed Res Int ; 2019: 9450240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854399

RESUMO

An increasing number of research studies over recent years have focused on the function of microRNA (miRNA) molecules which have unique characteristics in terms of structure and function. They represent a class of endogenous noncoding single-strand small molecules. An abundance of miRNA clusters has been found in the genomes of various organisms often located in a polycistron. The miR-17-92 family is among the most famous miRNAs and has been identified as an oncogene. The functions of this cluster, together with the seven individual molecules that it comprises, are most related to cancers, so it would not be surprising that they are considered to have involvement in the development of tumors. The miR-17-92 cluster is therefore expected not only to be a tumor marker, but also to perform an important role in the early diagnosis of those diseases and possibly also be a target for tumor biotherapy. The miR-17-92 cluster affects the development of disease by regulating many related cellular processes and multiple target genes. Interestingly, it also has important roles that cannot be ignored in disease of the nervous system and circulation and modulates the growth and development of bone. Therefore, it provides new opportunities for disease prevention, clinical diagnosis, prognosis, and targeted therapy. Here we review the role of the miR-17-92 cluster that has received little attention in relation to neurological diseases, cardiac diseases, and the development of bone and tumors.


Assuntos
Desenvolvimento Ósseo/genética , MicroRNAs/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Família Multigênica/genética , Neoplasias/patologia , Doenças do Sistema Nervoso/patologia , Prognóstico
11.
Biochimie ; 160: 172-182, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30890453

RESUMO

POSTN knockdown inhibits the formation of NLRP3 inflammasome in rat myocardium.Periostin (POSTN), an extracellular matrix protein, and peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated nuclear transcription factor, are reported to be involved in renal and cardiac dysfunction associated with chronic kidney disease (CKD), respectively. This study is performed to investigate how POSTN-PPARα axis affects the progress of CKD. In vivo, adenovirus particles containing POSTN short hairpin RNA (Ad-shPOSTN) were intravenously given to Sprague Dawley rats following 5/6 nephrectomy. The effects of Ad-shPOSTN on CKD and CKD-associated cardiovascular disease were evaluated. In vitro, NRK-52E renal tubular epithelial cells were infected with Ad-shPOSTN or Ad-POSTN (overexpression) to explore whether POSTN affected collagen deposition by regulating PPARα. We found that POSTN expression was upregulated, while PPARα was downregulated in the injured renal and left ventricular tissues of nephrectomized rats. Ad-shPOSTN improved renal function, prevented cardiac dysfunction, and attenuated organ fibrosis in nephrectomized rats. The expression levels of renal and myocardial PPARα were increased following Ad-shPOSTN administration. Furthermore, POSTN silencing suppressed the formation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the myocardium: the levels of NLRP3, anti-apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase 1, mature interleukin (IL)-1ß and IL-18 were reduced. In NRK-52E cells, forced overexpression of POSTN directly inhibited PPARα expression and induced collagen deposition. WY14643, a PPARα agonist, suppressed POSTN-induced collagen deposition. In summary, our study demonstrates that POSTN negatively regulates PPARα expression. Targeting POSTN-PPARα axis may present a novel protective intervention to alleviate CKD and CKD-associated cardiac dysfunction.


Assuntos
Moléculas de Adesão Celular/metabolismo , Cardiopatias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR alfa/metabolismo , Insuficiência Renal Crônica/patologia , Animais , Moléculas de Adesão Celular/genética , Células Cultivadas , Cardiopatias/genética , Cardiopatias/metabolismo , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nefrectomia , PPAR alfa/genética , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo
12.
Nature ; 566(7743): 264-269, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700906

RESUMO

The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1. Its hyperactivation contributes to disease in numerous organs, including the heart1,2, although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3ß) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3-9. Each kinase requires engagement of multiple serines, impeding analysis of their role in vivo. Here we show that phosphorylation or gain- or loss-of-function mutations at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) can bidirectionally control mTORC1 activity stimulated by growth factors or haemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remains unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide signalling, and protects against heart disease10-13. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knock-in mice that express a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that cannot be rescued by PKG1 stimulation. However, cardiac disease is reduced and survival of heterozygote Tsc2S1365A knock-in mice subjected to the same stress is improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (TSC2(S1365E)). Resting mTORC1 activity is not altered in either knock-in model. Therefore, TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. The serine residues identified here provide a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Cardiopatias/prevenção & controle , Cardiopatias/fisiopatologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/química , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Animais , Autofagia , Células Cultivadas , Progressão da Doença , Ativação Enzimática , Everolimo/farmacologia , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Hipertrofia/tratamento farmacológico , Hipertrofia/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos , Mutação , Miócitos Cardíacos/patologia , Fosforilação , Fosfosserina/metabolismo , Pressão , Ratos , Ratos Wistar , Serina/genética , Serina/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética
13.
PLoS One ; 14(1): e0210017, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30615648

RESUMO

The incidence of stillbirth in Sweden has essentially remained constant since the 1980's, and despite thorough investigation, many cases remain unexplained. It has been suggested that a proportion of stillbirth cases is caused by heart disease, mainly channelopathies. The aim of this study was to analyze DNA from 290 stillbirth cases without chromosomal abnormalities for pathogenic single nucleotide variants (SNVs) in 70 genes associated with cardiac channelopathies and cardiomyopathies. The HaloPlex Target Enrichment System (Agilent Technologies) was utilized to prepare sequencing libraries which were sequenced on the Illumina NextSeq platform. We found that 12.1% of the 290 investigated stillbirth cases had one (n = 31) or two (n = 4) variants with evidence supporting pathogenicity, i.e. loss-of-function variants (nonsense, frameshift, splice site substitutions), evidence from functional studies, or previous identification of the variants in affected individuals. Regarding identified putative pathogenic variants in genes associated with channelopathies, the prevalence was significantly higher in the stillbirth cohort (n = 23, 7.93%) than the corresponding prevalence of the same variants in the non-Finnish European population of the Exome Aggregation Consortium (2.70%, p<0.001) and SweGen, (2.30%, p<0.001). Our results give further support to the hypothesis that cardiac channelopathies might contribute to stillbirth. Screening for pathogenic SNVs in genes associated with heart disease might be a valuable complement for stillbirth cases where today's conventional investigation does not reveal the underlying cause of fetal demise.


Assuntos
Predisposição Genética para Doença/genética , Cardiopatias/genética , Mutação com Perda de Função , Polimorfismo de Nucleotídeo Único , Natimorto/genética , Cardiomiopatias/genética , Canalopatias/genética , Códon sem Sentido , Estudos de Coortes , Feminino , Mutação da Fase de Leitura , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Incidência , Natimorto/epidemiologia , Suécia/epidemiologia
14.
Cardiovasc Pathol ; 39: 12-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30594732

RESUMO

Lysosomal storage disorders (LSD) comprise a group of diseases caused by a deficiency of lysosomal enzymes, membrane transporters or other proteins involved in lysosomal biology. Lysosomal storage disorders result from an accumulation of specific substrates, due to the inability to break them down. The diseases are classified according to the type of material that is accumulated; for example, lipid storage disorders, mucopolysaccharidoses and glycoproteinoses. Cardiac disease is particularly important in lysosomal glycogen storage diseases (Pompe and Danon disease), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease). Various disease manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular diseases. Endomyocardial biopsies can play an important role in the diagnosis of these diseases. Microscopic features along with ancillary tests like special stains and ultrastructural studies help in the diagnosis of these disorders. Diagnosis is further confirmed based upon enzymatic and molecular genetic analysis. Emerging evidence suggests that Enzyme replacement therapy (ERT) substantially improves many of the features of the disease, including some aspects of cardiac involvement. The identification of these disorders is important due to the availability of ERT, the need for family screening, as well as appropriate patient management and counseling.


Assuntos
Cardiopatias/patologia , Doenças por Armazenamento dos Lisossomos/patologia , Miocárdio/patologia , Biópsia , Terapia de Reposição de Enzimas , Predisposição Genética para Doença , Cardiopatias/tratamento farmacológico , Cardiopatias/enzimologia , Cardiopatias/genética , Humanos , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/genética , Miocárdio/ultraestrutura , Fenótipo , Fatores de Risco , Resultado do Tratamento
15.
Physiol Rev ; 99(1): 381-426, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30379622

RESUMO

The sarcomeric proteins represent the structural building blocks of heart muscle, which are essential for contraction and relaxation. During recent years, it has become evident that posttranslational modifications of sarcomeric proteins, in particular phosphorylation, tune cardiac pump function at rest and during exercise. This delicate, orchestrated interaction is also influenced by mutations, predominantly in sarcomeric proteins, which cause hypertrophic or dilated cardiomyopathy. In this review, we follow a bottom-up approach starting from a description of the basic components of cardiac muscle at the molecular level up to the various forms of cardiac disorders at the organ level. An overview is given of sarcomere changes in acquired and inherited forms of cardiac disease and the underlying disease mechanisms with particular reference to human tissue. A distinction will be made between the primary defect and maladaptive/adaptive secondary changes. Techniques used to unravel functional consequences of disease-induced protein changes are described, and an overview of current and future treatments targeted at sarcomeric proteins is given. The current evidence presented suggests that sarcomeres not only form the basis of cardiac muscle function but also represent a therapeutic target to combat cardiac disease.


Assuntos
Proteínas de Transporte/metabolismo , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Miocárdio/metabolismo , Sarcômeros/metabolismo , Animais , Cardiopatias/genética , Humanos , Mutação/genética , Fosforilação/fisiologia
16.
Pharmacol Res ; 141: 104-113, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30579974

RESUMO

Dysregulated immune system has been implicated in the pathogenesis of various cardiovascular diseases. Therefore, development of pharmacological interventions targeting the immune system is promising. However, therapy with most common anti-inflammatory and immunomodulatory agents has proved challenging in the clinical translation. It has been proved that many herbal ingredients display definite therapeutic effects on preventing excessive inflammatory and immune responses. Here, we aim to systemically explore the immunomodulatory ability of herbal ingredients on the human heart tissue-specific immune dysfunction through a network pharmacology based approach. The approach matches gene expression data between herbal ingredients and human heart phenotype based on their immunological similarities. Firstly, 608 immunological signatures were produced from 304 transcriptional profiles of immunological cell state changes. Then, the immunological features of 28 human heart phenotypes and 102 herbal ingredients were constructed by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients, respectively. Finally, the likelihood that an herbal drug affects the immune system in a heart phenotype was qualified by calculating the immunological similarity between the herbal drug and the heart phenotype. This strategy integrating different types of OMICs data is expected to help create new opportunities for development of drugs targeting the immune dysfunction in heart disease.


Assuntos
Cardiopatias/genética , Cardiopatias/imunologia , Fatores Imunológicos/farmacologia , Miocárdio/imunologia , Preparações de Plantas/farmacologia , Transcriptoma/efeitos dos fármacos , Humanos , Fenótipo
17.
Development ; 145(24)2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30573475

RESUMO

Embryonic and postnatal life depend on the uninterrupted function of cardiac muscle cells. These cells, termed cardiomyocytes, display many fascinating behaviors, including complex morphogenic movements, interactions with other cell types of the heart, persistent contractility and quiescence after birth. Each of these behaviors depends on complex interactions between both cardiac-restricted and widely expressed transcription factors, as well as on epigenetic modifications. Here, we review recent advances in our understanding of the genetic and epigenetic control of cardiomyocyte differentiation and proliferation during heart development, regeneration and disease. We focus on those regulators that are required for both heart development and disease, and highlight the regenerative principles that might be manipulated to restore function to the injured adult heart.


Assuntos
Epigênese Genética , Cardiopatias/genética , Coração/embriologia , Miócitos Cardíacos/metabolismo , Regeneração/genética , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos
19.
Chemosphere ; 212: 915-926, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30286548

RESUMO

PM2.5 exposure is strongly linked to cardiac disease. Subtle epigenetic or transcriptional alterations induced by PM2.5 might contribute to pathogenesis and disease susceptibility of cardiac disease. It is still a major challenge to identify biological targets in human genetics. Human cardiomyocytes AC16 was chosen as cell model. Epigenetic effect of PM2.5 in AC16 was analyzed using Illumina HumanMethylation 450 K BeadChip. Meanwhile the transcriptomic profiling was performed by Affymetrix® microarray. PM2.5 induced genome wide variation of DNA methylation pattern, including differentially methylated CpGs in promoter region. Then gene ontology analysis demonstrated differentially methylated genes were significantly clustered in pathways in regulation of apoptotic process, cell death and metabolic pathways, or associated with ion binding and shuttling. Correlation of the methylome and transcriptome revealed a clear bias toward transcriptional suppression by hypermethylation or activation by hypomethylation. Identified 386 genes which exhibited both differential methylation and expression were functionally associated with pathways including cardiovascular system development, regulation of blood vessel size, vasculature development, p53 pathway, AC-modulating/inhibiting GPCRs pathway and cellular response to metal ion/inorganic substance. Disease ontology demonstrated their prominent role in cardiac diseases and identified 14 cardiac-specific genes (ANK2, AQP1 et al.). PPI network analysis revealed 6 novel genes (POLR2I, LEP, BRIX1, ADCY6, INSL3, RARS). Those genes were then verified by qRT-PCR. Thus, in AC16, PM2.5 alters the methylome and transcriptome of genes might be relevant for PM2.5-/heart-associated diseases. Result gives additional insight in PM2.5 relative cardiac diseases/associated genes and the potential mechanisms that contribute to PM2.5 related cardiac disease.


Assuntos
Metilação de DNA/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Cardiopatias/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Tamanho da Partícula , Material Particulado/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/genética , Epigênese Genética/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Humanos , Miócitos Cardíacos/patologia , Material Particulado/química , Mapas de Interação de Proteínas/efeitos dos fármacos
20.
Med. clín (Ed. impr.) ; 151(7): 270-274, oct. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-173947

RESUMO

Fundamento y objetivos: Estudiar la frecuencia de mutaciones relacionadas con cardiopatías genéticas entre los pacientes jóvenes atendidos por un síncope durante la práctica de deporte. Pacientes y métodos: Estudio de una serie de casos que incluyó a pacientes≤45 años con un síncope relacionado con la práctica del deporte durante 2010-2011. Se recogieron variables demográficas, clínicas, mutaciones genéticas y diagnóstico clínico final. Resultados: Se realizó un test genético en 46 (76,7%) de los 60 pacientes evaluados. El test genético fue positivo en 12 (26%; IC 95% 15,6-40,3) pacientes, de los cuales 10 (21,7%) tuvieron una mutación para el gen PKP2 de displasia arritmogénica de ventrículo derecho, uno (2,2%) para el gen KCNQ1 y otro (2,2%) para el gen SCN5A, relacionados con canalopatías. El test genético fue positivo en 11 (35,5%) casos con síncope indeterminado y en un (50%) caso con síncope cardiogénico, siendo negativo en todos los casos de síncope neuromediado (p=0,037). Conclusiones: Las mutaciones genéticas son frecuentes en pacientes jóvenes que presentan un síncope durante la práctica deportiva, especialmente en aquellos con etiología cardiaca o indeterminada


Background and objectives: To study the frequency of genetic mutations related to genetic heart disease among young patients admitted for syncope during sport practice. Patients and methods: A case series study that included patients≤45 years admitted for syncope during sport practice during 2010-2011. We collected demographic and clinical variables, genetic tests mutations and final clinical diagnosis. Results: A genetic test was performed in 46 (76.7%) of 60 patients evaluated. The genetic test was positive in 12 (26%; 95% CI 15.6-40.3) patients; 10 (21.7%) had PKP2 mutation related to arrhythmogenic right ventricular dysplasia mutation, one (2.2%) KCNQ1 mutation and one (2.2%) SCN5A mutation related to channelopathies. The genetic test was positive in 11 (35.5%) cases of undetermined syncope and one (50%) case of cardiac syncope, being negative in all cases with neuromediated syncopes (P=.037). Conclusions: Gene mutations are common in young patients suffering from syncope during sports, especially in those with cardiac or undetermined aetiology


Assuntos
Humanos , Masculino , Feminino , Adulto , Síncope/etiologia , Morte Súbita Cardíaca/etiologia , Mutação/genética , Serviços Médicos de Emergência/métodos , Esportes , Cardiopatias/genética , Morte Súbita Cardíaca/epidemiologia , Epidemiologia Descritiva
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