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1.
Am Heart J ; 220: 213-223, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31864099

RESUMO

BACKGROUND: Cardiogenic syncope in Brugada syndrome (BrS) increases the risk of major events. Nevertheless, clinical differentiation between cardiogenic and vasovagal syncope can be challenging. We characterized the long-term incidence of major events in a large cohort of BrS patients who presented with syncope. METHODS: From a total of 474 patients, syncope was the initial manifestation in 135 (28.5%) individuals (43.9 ±â€¯13.9 years, 71.1% male). The syncope was classified prospectively as cardiogenic, vasovagal, or undefined if unclear characteristics were present. Clinical, electrocardiographic, genetic, and electrophysiologic features were analyzed. Cardiogenic syncope, sustained ventricular arrhythmias, and sudden death were considered major events in follow-up. RESULTS: In 66 patients (48.9%), the syncope was cardiogenic; in 51 (37.8%), vasovagal and in 18 (13.3%); undefined. The electrophysiology study (EPS) inducibility was more frequent in patients with cardiogenic syncope and absent in all patients with undefined syncope (28 [53.8%] vs 5 [12.2%] vs 0 [0%]; P < .01). During follow-up (7.7 ±â€¯5.6 years), only patients with cardiogenic syncope presented major events (16 [11.9%]). Among patients with inducible EPS, 7 (21.2%) presented major events (P = .04). The negative predictive value of the EPS for major events was 92.4%. The incidence rate of major events was 2.6% person-year. Parameters associated with major events included cardiogenic syncope (hazard ratio [HR] 6.3; 95% CI 1.1-10.4; P = .05), spontaneous type 1 electrocardiogram (HR 3.7; 95% CI 1.3-10.5; P = .01), and inducible EPS (HR 2.8; 95% CI 1.1-8.8; P = .05). CONCLUSIONS: An accurate syncope classification is crucial in BrS patients for risk stratification. In patients with syncope of unclear characteristics, the EPS may be helpful to prevent unnecessary implantable cardioverter defibrillators.


Assuntos
Síndrome de Brugada/complicações , Síncope/etiologia , Adulto , Arritmias Cardíacas/etiologia , Síndrome de Brugada/fisiopatologia , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Valor Preditivo dos Testes , Prevalência , Síncope/classificação , Síncope/epidemiologia , Síncope/fisiopatologia , Síncope Vasovagal/epidemiologia , Síncope Vasovagal/etiologia , Síncope Vasovagal/fisiopatologia , Teste da Mesa Inclinada
2.
Int J Mol Sci ; 20(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590245

RESUMO

Brugada syndrome (BrS) is marked by an elevated ST-segment elevation and increased risk of sudden cardiac death. Variants in the SCN5A gene are considered to be molecular confirmation of the syndrome in about one third of cases, while the genetics remain a mystery in about half of the cases, with the remaining cases being attributed to variants in any of a number of genes. Before research models can be developed, it is imperative to understand the genetics in patients. Even data from humans is complicated, since variants in the most common gene in BrS, SCN5A, are associated with a number of pathologies, or could even be considered benign, depending on the variant. Here, we provide crucial human data on a novel NM_198056.2:c.2091G>A (p.Trp697X) point-nonsense heterozygous variant in the SCN5A gene, as well as its segregation with BrS. The results herein suggest a pathogenic effect of this variant. These results could be used as a stepping stone for functional studies to better understand the molecular effects of this variant in BrS.


Assuntos
Síndrome de Brugada/genética , Códon sem Sentido , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adulto , Síndrome de Brugada/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
3.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614475

RESUMO

Dysfunction of the cardiac sodium channel Nav1.5 (encoded by the SCN5A gene) is associated with arrhythmias and sudden cardiac death. SCN5A mutations associated with long QT syndrome type 3 (LQT3) lead to enhanced late sodium current and consequent action potential (AP) prolongation. Internalization and degradation of Nav1.5 is regulated by ubiquitylation, a post-translational mechanism that involves binding of the ubiquitin ligase Nedd4-2 to a proline-proline-serine-tyrosine sequence of Nav1.5, designated the PY-motif. We investigated the biophysical properties of the LQT3-associated SCN5A-p.Y1977N mutation located in the Nav1.5 PY-motif, both in HEK293 cells as well as in newly generated mice harboring the mouse homolog mutation Scn5a-p.Y1981N. We found that in HEK293 cells, the SCN5A-p.Y1977N mutation abolished the interaction between Nav1.5 and Nedd4-2, suppressed PY-motif-dependent ubiquitylation of Nav1.5, and consequently abrogated Nedd4-2 induced sodium current (INa) decrease. Nevertheless, homozygous mice harboring the Scn5a-p.Y1981N mutation showed no electrophysiological alterations nor changes in AP or (late) INa properties, questioning the in vivo relevance of the PY-motif. Our findings suggest the presence of compensatory mechanisms, with additional, as yet unknown, factors likely required to reduce the "ubiquitylation reserve" of Nav1.5. Future identification of such modulatory factors may identify potential triggers for arrhythmias and sudden cardiac death in the setting of LQT3 mutations.


Assuntos
Substituição de Aminoácidos , Síndrome do QT Longo/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Motivos de Aminoácidos , Animais , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ligação Proteica , Ubiquitinação , Adulto Jovem
4.
Cardiol Young ; 29(10): 1257-1263, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31477192

RESUMO

INTRODUCTION: The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest. METHODS: A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing. RESULTS: All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination. CONCLUSIONS: There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.


Assuntos
Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , DNA/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adolescente , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/metabolismo , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Ecocardiografia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Linhagem , Fenótipo , Adulto Jovem
5.
Int Heart J ; 60(4): 979-982, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257342

RESUMO

Congenital long QT syndrome (LQTS) is a cardiac channelopathy that leads to the prolongation of the QT interval. This prolongation can lead to ventricular tachyarrhythmia, syncope, and sudden cardiac death. There are various types of LQTS. Treatment of LQT1 and LQT2 is mainly based on antiadrenergic therapy. LQT3, on the other hand, is a result of a mutation of the SCN5A gene, which encodes the sodium channels. In this type, patients are sensitive to vagal stimuli and episodes tend to occur at rest. Sodium channel blocking compounds, such as ranolazine, mexiletine, and flecainide, have been found to be effective in selective mutations.In this case report, we report the case of a child with congenital LQT3 (V411M) who presented first with sudden cardiac death and three weeks later with an implantable cardioverter defibrillator storm. Knowing the specific mutation and understanding the mechanism at the molecular level through an in vitro study yielded a clinically meaningful result. The patient's arrhythmia burden was totally eliminated following successful treatment with flecainide.


Assuntos
DNA/genética , Eletrocardiografia , Flecainida/uso terapêutico , Síndrome do QT Longo/tratamento farmacológico , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Criança , Análise Mutacional de DNA , Feminino , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
6.
BMC Cardiovasc Disord ; 19(1): 104, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046686

RESUMO

Arrhythmic sudden cardiac death (SCD) represents a major worldwide public health problem accounting for 15-20% of deaths. Risk stratification to identify patients at risk of SCD is crucial in order to implement preventive measures in the general population. Several biomarkers have been tested exploring different pathophysiological mechanisms of cardiac conditions. Conflicting results have been described limiting so far their use in clinical practice. The use of new biomarkers such as microRNAs and sex hormones and the emerging role of genetic on risk prediction of SCD is a current research topic showing promising results.This review outlines the role of plasma biomarkers to predict ventricular arrhythmias and SCD in non coronary artery disease with a special focus on their relationship with the genetic biomarkers.


Assuntos
Arritmias Cardíacas/etiologia , Morte Súbita Cardíaca/etiologia , Marcadores Genéticos , Arritmias Cardíacas/sangue , Arritmias Cardíacas/genética , Arritmias Cardíacas/mortalidade , Ácidos Graxos/sangue , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/sangue , Humanos , Mediadores da Inflamação/sangue , MicroRNAs/genética , Técnicas de Diagnóstico Molecular , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Peptídeo Natriurético Encefálico/sangue , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco
7.
Acta Biochim Biophys Sin (Shanghai) ; 51(6): 562-570, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31139826

RESUMO

The protein voltage-gated sodium channel Nav1.5 is highly upregulated in various types of cancer and, in general, promotes cancer cell invasiveness and metastatic progression. A previous study found that Nav1.5 was highly expressed in poorly differentiated oral squamous cell carcinoma (OSCC). However, whether Nav1.5 enhances invasiveness and metastasis of OSCC are still unknown. In this study, we found that Nav1.5 was highly expressed in OSCC cell lines compared with normal oral keratinocyte HOK cell line by using western blot analysis. CCK-8 assay results revealed that downregulation of Nav1.5 expression by its specific siRNA reduced proliferation of OSCC HSC-3 cells. Moreover, transwell assay results showed Nav1.5 knockdown significantly inhibited migration and invasion of HSC-3 cells. Meanwhile, qRT-PCR and western blot analysis results showed that epidermal growth factor (EGF) induced Nav1.5 expression in a time- and dose-dependent manner. In addition, EGF promoted proliferation, migration and invasion of HSC-3 cells. Importantly, the Nav1.5 inhibitor tetrodotoxin significantly inhibited the proliferation of HSC-3 cells and impeded the migration and invasion of HSC-3 cells. Furthermore, it was found that siRNA-mediated knockdown of Nav1.5 also lessened the proliferation of HSC-3 cells and blocked the migration and invasion of HSC-3 cells. Taken together, these results indicate that Nav1.5 is involved in the progression of OSCC and Nav1.5 promotes the proliferation, migration and invasion of OSCC cells.


Assuntos
Carcinoma de Células Escamosas/genética , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Bucais/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Invasividade Neoplásica , Interferência de RNA , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia
8.
Nat Commun ; 10(1): 2267, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118417

RESUMO

Mutations in LMNA, which encodes the nuclear proteins Lamin A/C, can cause cardiomyopathy and conduction disorders. Here, we employ induced pluripotent stem cells (iPSCs) generated from human cells carrying heterozygous K219T mutation on LMNA to develop a disease model. Cardiomyocytes differentiated from these iPSCs, and which thus carry K219T-LMNA, have altered action potential, reduced peak sodium current and diminished conduction velocity. Moreover, they have significantly downregulated Nav1.5 channel expression and increased binding of Lamin A/C to the promoter of SCN5A, the channel's gene. Coherently, binding of the Polycomb Repressive Complex 2 (PRC2) protein SUZ12 and deposition of the repressive histone mark H3K27me3 are increased at SCN5A. CRISPR/Cas9-mediated correction of the mutation re-establishes sodium current density and SCN5A expression. Thus, K219T-LMNA cooperates with PRC2 in downregulating SCN5A, leading to decreased sodium current density and slower conduction velocity. This mechanism may underlie the conduction abnormalities associated with LMNA-cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/genética , Sistema de Condução Cardíaco/patologia , Lamina Tipo A/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Adolescente , Adulto , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/cirurgia , Linhagem Celular , Regulação para Baixo , Epigênese Genética , Feminino , Transplante de Coração , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Pessoa de Meia-Idade , Mutação , Miocárdio/citologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Complexo Repressor Polycomb 2/metabolismo
9.
Nat Commun ; 10(1): 1514, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944319

RESUMO

Skeletal muscle voltage-gated Na+ channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca2+-dependent inactivation; no such inactivation is observed in the cardiac Na+ channel (NaV1.5). Taken together, the crystal structures of the NaV1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca2+-dependent CaM N-lobe binding site previously identified in NaV1.5 is not present in NaV1.4 allowing the N-lobe to signal other regions of the NaV1.4 channel. Consistent with this mechanism, removing this binding site in NaV1.5 unveils robust Ca2+-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca2+-dependent inactivation is effected by CaM's N-lobe binding outside the NaV C-terminal while CaM's C-lobe remains bound to the NaV C-terminal. As the N-lobe binding motif of NaV1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.


Assuntos
Cálcio/metabolismo , Calmodulina/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Sítios de Ligação , Cálcio/química , Calmodulina/química , Calmodulina/genética , Humanos , Modelos Moleculares , Músculo Esquelético/metabolismo , Mutação , Canal de Sódio Disparado por Voltagem NAV1.4/química , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas
10.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31032819

RESUMO

Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.


Assuntos
Síndrome de Brugada/etiologia , Síndrome de Brugada/fisiopatologia , Modelos Animais de Doenças , Animais , Animais Geneticamente Modificados , Biomarcadores , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/terapia , Diferenciação Celular , Suscetibilidade a Doenças , Cães , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Mutação , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética
11.
Rev. esp. cardiol. (Ed. impr.) ; 72(4): 324-332, abr. 2019. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187898

RESUMO

Introducción y objetivos: En 4 miembros de una familia española se identificó una mutación en los canales cardiacos Nav1.5 (p.R1644H) descrita ya y relacionada con el síndrome de QT largo con anterioridad. Sin embargo, solo 1 de los portadores presentaba el intervalo QT prolongado. En los otros 3 individuos se identificó una nueva mutación con cambio de sentido en los canales cardiacos Cav1.2 (p.S1961N). En este trabajo se analizaron las características funcionales de los canales p.S1961N Cav1.2 para averiguar si dicha mutación regula la expresividad del síndrome de QT largo en esta familia. Métodos: La corriente de calcio tipo L (ICaL) se registró mediante la técnica de patch-clamp en células de ovario de hámster chino transfectadas transitoriamente con los canales cardiacos humanos en su forma nativa o mutada. Resultados: La expresión de canales p.S1961N disminuye significativamente la densidad de la ICaL. Al sustituir el ion calcio por bario para suprimir la inactivación dependiente del calcio de los canales Cav1.2, se demostró que la mutación acelera significativamente la inactivación dependiente del voltaje de los canales Cav1.2 y disminuye la constante de tiempo de inactivación. Como consecuencia, la carga total que atraviesa los canales p.S1961N Cav1.2 disminuye significativamente. Los efectos que las mutaciones p.S1961N Cav1.2 y p.R1644H Nav1.5, por separado o en combinación, producen sobre las características de los potenciales de acción (PA) se simularon mediante un modelo matemático de PA ventriculares humanos. Los resultados demuestran que la mutación p.S1961N Cav1.2 abrevia la duración del PA y suprime la prolongación inducida por la mutación p.R1644H de los canales Nav1.5. Conclusiones: La mutación p.S1961N en los canales Cav1.2 disminuye la ICaL, un efecto que podría abreviar la duración de los PA ventriculares humanos. La presencia de esta mutación que disminuye la función de los canales Cav1.2 compensa funcionalmente los efectos producidos por la mutación de los canales Nav1.5 que aumenta su función y prolonga la duración de los PA


Introduction and objectives: A known long QT syndrome-related mutation in Nav1.5 cardiac channels (p.R1644H) was found in 4 members of a Spanish family but only 1 of them showed prolongation of the QT interval. In the other 3 relatives, a novel missense mutation in Cav1.2 cardiac channels was found (p.S1961N). Here, we functionally analyzed p.S1961N Cav1.2 channels to elucidate whether this mutation regulates the expressivity of the long QT syndrome phenotype in this family. Methods: L-type calcium current (ICaL) recordings were performed by using the whole-cell patch-clamp technique in Chinese hamster ovary cells transiently transfected with native and/or p.S1961N Cav1.2 channels. Results: Expression of p.S1961N channels significantly decreased ICaL density. Using Ba as a charge carrier to suppress the Ca-dependent inactivation of Cav1.2 channels, we demonstrated that the mutation significantly accelerates the voltage-dependent inactivation of Cav1.2 channels decreasing the inactivation time constant. As a consequence, the total charge flowing through p.S1961N Cav1.2 channels significantly decreased. The effects of the p.S1961N Cav1.2 and p.R1644H Nav1.5 mutations alone or their combination on the action potential (AP) morphology were simulated using a validated model of the human ventricular AP. The p.S1961N Cav1.2 mutation shortens the AP duration and abrogates the prolongation induced by p.R1644H Nav1.5 channels. Conclusions: The p.S1961N mutation in Cav1.2 channels decreased the ICaL, an effect which might shorten ventricular AP. The presence of the loss-of-function Cav1.2 mutation could functionally compensate the prolonging effects produced by the Nav1.5 gain-of-function mutation


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Síndrome do QT Longo/genética , Heterozigoto , Transfecção/métodos , Mutagênese/genética , Canalopatias/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Doenças Genéticas Inatas , Mutação/genética , Eletrocardiografia/estatística & dados numéricos , Testes Genéticos/métodos , Técnicas de Patch-Clamp/métodos , Morte Súbita Cardíaca
13.
Cardiovasc J Afr ; 30(2): 79-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30882133

RESUMO

AIM: We aimed to study the effect of allocryptopine (All) on the late sodium current (INa,Late) of atrial myocytes in spontaneously hypertensive rats (SHR). METHODS: The enzyme digestion method was used to separate single atrial myocytes from SHR and Wistar-Kyoto (WKY) rats. INa,Late was recorded using the patch-clamp technique, and the effect of All was evaluated on the current. RESULTS: Compared with WKY rat cells, an increase in the INa,Late current in SHR myocytes was found. After treatment with 30 µM All, the current densities were markedly decreased; the ratio of INa,Late/INa,peak of SHR was reduced by 30 µM All. All reduced INa,Late by alleviating inactivation of the channel and increasing the window current of the sodium channel. Furthermore, INa,Late densities of three SCN5A mutations declined substantially with 30 µM All in a concentration-dependent manner. CONCLUSIONS: The results clearly show that an increase in INa,Late in SHR atrial myocytes was inhibited by All derived from Chinese herbal medicine.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/prevenção & controle , Alcaloides de Berberina/farmacologia , Átrios do Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/efeitos dos fármacos , Sódio/metabolismo , Potenciais de Ação , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Átrios do Coração/metabolismo , Frequência Cardíaca , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Mutação , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores de Tempo
14.
Cell Mol Biol (Noisy-le-grand) ; 65(2): 58-62, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30860472

RESUMO

To investigate the expressions of Nav1.5 mRNA at different time points in a rat model of temporal lobe epilepsy (TLE), and to assess the potential contribution of Nav1.5 to epileptogenesis. Male Sprague-Dawley rats (72) weighing 230 to 250 g were used for this study. They were randomly assigned to six groups (12 rats/group): control and five TLE groups. The TLE groups were day 1 (acute period), days 7 and 14 (latent period), and days 30 and 60 (chronic period). With the exception of control, epilepsy was induced in the rats with an intraperitoneal (i.p.) injection of aqueous solution of lithium chloride 18 h prior to pilocarpine injection (i.p.) at a dose of 125 mg/kg body weight (b.wt). Rats in the control group were injected i.p. with 0.9 % sodium chloride (125 mg/kg b.wt.) in place of pilocarpine. A total of 84 out of 112 rats developed status epilepticus (SE). The expression of Nav1.5 in the brains of rats was assessed using quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blot analysis. The expressions of Scn5a mRNA in the hippocampus during the latent and chronic periods were significantly higher than in the control group (p < 0.05), but there were no significant differences in the corresponding expressions between the two different time points in the latent and chronic period groups (p > 0.05). The expression peaked 30 days post-SE, and was sustained for 60 days. There was no significant difference in the expression of Scn5a mRNA in the acute group, when compared to control. Immunohistochemical staining showed that expression levels of Nav1.5 in the CA3 region during latent and chronic periods were significantly higher than those in control group (p < 0.05), and the expressions peaked at day 30. However, there was no significant difference in the expression of Nav1.5 in the latent group, relative to the chronic period group. These results show that Nav1.5 might be involved in the pathogenesis of TLE.


Assuntos
Epilepsia do Lobo Temporal/patologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Animais , Epilepsia do Lobo Temporal/genética , Regulação da Expressão Gênica , Hipocampo/metabolismo , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
15.
Proc Natl Acad Sci U S A ; 116(8): 2945-2954, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30728299

RESUMO

The human voltage-gated sodium channel, hNaV1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNaV1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNaV1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNaV1.5 and will be useful for rational design of novel therapeutics.


Assuntos
Antiarrítmicos/química , Simulação de Dinâmica Molecular , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canais de Sódio/química , Sequência de Aminoácidos/genética , Antiarrítmicos/uso terapêutico , Sítios de Ligação , Interações Medicamentosas , Flecainida/química , Humanos , Lidocaína/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Sódio/química , Canais de Sódio/genética
16.
Rev Esp Cardiol (Engl Ed) ; 72(4): 333-340, 2019 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30792015

RESUMO

Dilated cardiomyopathy is inherited in nearly 50% of cases. More than 90 genes have been associated with this disease, which is one of the main causes of heart transplant and has been associated with an increased risk of sudden cardiac death. Risk stratification in these patients continues to be challenging. The identification of the specific etiology of the disease is very useful for the early detection of mutation carriers. Genetic study often provides prognostic information and can determine the therapeutic approach. Wide phenotypic variability is observed depending on the mutated gene, the type of mutation, and the presence of additional genetic and environmental factors.


Assuntos
Cardiomiopatia Dilatada/genética , Testes Genéticos/métodos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas do Citoesqueleto/genética , Desmossomos/genética , Filaminas/genética , Genes , Genes Mitocondriais/genética , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Prognóstico , Proteínas de Ligação a RNA/genética , Medição de Risco , Sarcômeros/genética
17.
QJM ; 112(5): 343-350, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690642

RESUMO

BACKGROUND: Brugada syndrome (BrS) is a heritable sudden cardiac death (SCD) disease with male predominance. Information on gender difference of BrS remains scarce. AIM: To investigate the gender difference of BrS in Han Chinese. DESIGN: We consecutively enrolled 169 BrS patients (153 males and 16 females) from Han Chinese in Taiwan from 1998 to 2017. METHODS: Clinical characteristics, electrocardiographic parameters and SCN5A mutation status were compared between genders. RESULTS: The percentage of family history of SCD in females was slightly higher (31.3% vs. 15%, P = 0.15). Females exhibited longer QTc (457.8 ± 33.0 vs. 429.5 ± 42.1 ms, P < 0.01). Regarding cumulative event occurrence by age, Mantel-Cox test showed females had earlier age of onset of first cardiac events (SCD or syncope) than males (P = 0.049), which was mainly attributed to syncope (P < 0.01). Males with SCD exhibited longer QRS duration (114.2 ± 26.8 vs. 104.8 ± 15.3 ms, P = 0.02) and QTc (442.5 ± 57.4 vs. 422.9 ± 28.8 ms, P = 0.02). Males with syncope exhibited longer PR interval (181.2 ± 33.7 vs. 165.7 ± 27.1 ms, P = 0.01), whereas females with SCD or syncope had a trend towards slower heart rates (69.1 ± 9.6 vs. 82.2 ± 16.3 bpm, P = 0.10) than female with no or mild symptoms. There was no difference in the percentage of SCN5A mutation between genders. CONCLUSION: Gender difference is present in BrS. Females have longer QTc and suffer from syncope earlier than males. Risk of SCD in males is associated with boarder QRS complex and longer QTc, whereas risk of syncope is associated with longer PR interval in males and slower heart rate in females.


Assuntos
Síndrome de Brugada/genética , Morte Súbita Cardíaca/epidemiologia , Síndrome do QT Longo/epidemiologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Fatores Sexuais , Síncope/etiologia , Adulto , Síndrome de Brugada/complicações , Síndrome de Brugada/fisiopatologia , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Feminino , Humanos , Síndrome do QT Longo/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Sistema de Registros , Medição de Risco , Distribuição por Sexo , Síncope/epidemiologia , Taiwan/epidemiologia
18.
Am J Physiol Heart Circ Physiol ; 316(2): H371-H379, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30499712

RESUMO

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.


Assuntos
Fibrilação Atrial/genética , Proteína 1A de Ligação a Tacrolimo/metabolismo , Potenciais de Ação , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Células Cultivadas , Átrios do Coração/citologia , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Proteína 1A de Ligação a Tacrolimo/genética
19.
Immunobiology ; 224(1): 80-93, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391100

RESUMO

Prior work demonstrated that a splice variant of SCN5A, a voltage-gated sodium channel gene, acts as a cytoplasmic sensor for viral dsRNA in human macrophages. Expression of this channel also polarizes macrophages to an anti-inflammatory phenotype in vitro and in vivo. Here we utilized global expression analysis of splice variants to identify novel channel-dependent signaling mechanisms. Pharmacological activation of voltage-gated sodium channels in human macrophages, but not treatment with cytoplasmic poly I:C, was associated with splicing of a retained intron in transcripts of PPP1R10, a regulator of phosphatase activity and DNA repair. Microarray analysis also demonstrated expression of a novel sodium channel splice variant, human macrophage SCN10A, that contains a similar exon deletion as SCN5A. SCN10A localizes to cytoplasmic and nuclear vesicles in human macrophages. Simultaneous expression of human macrophage SCN5A and SCN10A was required to decrease expression of the retained intron and increase protein expression of PPP1R10. Channel activation also increased protein expression of the splicing factor EFTUD2, and knockdown of EFTUD2 prevented channel dependent splicing of the retained PPP1R10 intron. Knockdown of the SCN5A and SCN10A variants in human macrophages reduced the severity of dsDNA breaks induced by treatment with bleomycin and type 1 interferon. These results suggested that human macrophage SCN5A and SCN10A variants mediate an innate immune signaling pathway that limits DNA damage through increased expression of PPP1R10. The functional significance of this pathway is that it may prevent cytotoxicity during inflammatory responses.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inflamação/metabolismo , Macrófagos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Fatores de Alongamento de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Células Cultivadas , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Inflamação/genética , Análise em Microsséries , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Fatores de Alongamento de Peptídeos/genética , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Transdução de Sinais , Regulação para Cima
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