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1.
Yakugaku Zasshi ; 139(5): 793-805, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31061349

RESUMO

Angiotensin II (Ang II) is an intrinsic peptide having strong vasopressor effects, and thus, it plays an important role in the physiological regulation of blood pressure. The vasopressor effects of Ang II include direct contraction of myocardium and vascular smooth muscles (SMs) along with aldosterone-mediated sodium retention. In addition, indirect vascular contractions induced by noradrenaline (NA), the release of which is mediated through Ang II receptor type 1 (AT1) existing at the sympathetic nerve terminals (SNTs), also contribute to the vasopressor effects of Ang II. Stimulation of NA release from SNTs by Ang II also occurs in the myocardium leading to an increase in heart rate and cardiac contraction. Furthermore, Ang II enhances the contractions of non-vascular SMs, such as vas deferens, through induction of NA release from the SNTs. We have found that Ang II attenuated vagus nerve stimulation-induced bradycardia in a losartan-sensitive manner. This suggests that Ang II attenuates vagus nerve stimulation-induced bradycardia by inhibiting acetylcholine (ACh) release from the parasympathetic nerve terminals (PNTs) through activation of the AT1 receptor. Ang II was also reported to attenuate the release of ACh from the PNTs in SMs, such as stomach and airway, thus suppressing their contractile functions. There are, however, conflicting reports of the effects of Ang II on parasympathetic nerve-mediated contractile regulation of SMs. In this review, we have highlighted the relevant research articles including our experimental reports on the regulation of sympathetic and parasympathetic nerve-mediated excitation and contraction by Ang II along with the future prospects.


Assuntos
Angiotensina II/fisiologia , Vias Autônomas/fisiologia , Músculo Liso/fisiologia , Contração Miocárdica/genética , Contração Miocárdica/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Sistema Nervoso Simpático/fisiologia , Transmissão Sináptica/genética , Acetilcolina/metabolismo , Angiotensina II/biossíntese , Animais , Frequência Cardíaca/genética , Humanos , Norepinefrina/metabolismo , Ratos , Sistema Nervoso Simpático/metabolismo
2.
Acta Diabetol ; 56(9): 1037-1044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30989380

RESUMO

AIMS: Observational studies indicated that resting heart rate (RHR) was associated with diabetes mellitus (DM) risk; however, it remains unclear whether the association between RHR and DM is causal. We aimed to examine whether there was causal association of RHR with DM risk. METHODS: A prospective study including 16,201 middle-aged and older Chinese (7031 males and 9170 females) derived from the Dongfeng-Tongji cohort was performed. Cox proportional hazard regression models were conducted to estimate the associations between RHR and incident DM risk. In 7481 participants, 65 single nucleotide polymorphisms related to RHR were genotyped. A genetic risk score (GRS) of RHR was calculated based on the RHR-associated variants. The causal associations of RHR with DM risk were investigated by Mendelian randomization analysis. RESULTS: During a mean (SD) follow-up of 4.5 (0.5) years, 1110 diabetes were identified. Compared with the referential RHR group (≤ 60 beats per minute [bpm]), individuals with RHR > 80 bpm have a higher incident diabetes risk, with a hazard ratio of 1.40 (95% confidence interval [CI], 1.05-1.88). With per SD increase in the weighted genetic risk score, the resting heart rate increased by 0.71 bpm (95% CI 0.49-0.93). By using the GRS to estimate the unconfounded effect, we found that higher resting heart rate did not have a causal effect on diabetes risk (OR 1.00 [95% CI 0.95-1.05]). CONCLUSIONS: The present study supported a positive but not a causal association of RHR with incident diabetes risk. More studies are needed to verify our findings.


Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Frequência Cardíaca/genética , Polimorfismo de Nucleotídeo Único , Descanso/fisiologia , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , China/epidemiologia , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
3.
PLoS Biol ; 17(3): e3000161, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30822301

RESUMO

Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1-/-;Adora2a-/-;Adora2b-/-;Adora3-/- (quad knockout [QKO]), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5'-monophosphate (AMP)-induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature.


Assuntos
Hipotermia/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Animais , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Temperatura Corporal/genética , Temperatura Corporal/fisiologia , Cafeína/farmacologia , Feminino , Genótipo , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Hipotermia/induzido quimicamente , Hipotermia/genética , Inosina/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Receptor A1 de Adenosina/genética , Receptor A2A de Adenosina/genética , Receptor A2B de Adenosina/genética , Receptor A3 de Adenosina/genética , Uridina/toxicidade
4.
J Pharmacol Exp Ther ; 369(1): 129-141, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30728249

RESUMO

In an integrative approach, we studied the role of histamine H2 receptors in the mouse heart. We noted that histamine, added cumulatively to the organ bath, failed to affect the force of contraction in left atrial preparations and did not change spontaneous heart rate in right atrial preparations from wild-type mice. By contrast, in the same preparations from mice that overexpressed the human H2 receptor in a cardiac-specific way, histamine exerted concentration- and time-dependent positive inotropic and positive chronotropic effects. Messenger RNA of the human H2 receptor was only detected in transgenic mice. Likewise, immunohistology and autoradiography only gave signals in transgenic but not in wild-type cardiac preparations. Similarly, a positive inotropic and positive chronotropic effect was observed with histamine in echocardiography of living transgenic mice and isolated perfused hearts (Langendorff preparation). Phosphorylation of phospholamban was increased in atrial and ventricular preparations from transgenic mice, but not in wild-type animals. The effects of histamine were mimicked by dimaprit and amthamine and antagonized by cimetidine. In summary, we generated a new model to study the physiologic and pathophysiologic cardiac role of the human H2 receptor.


Assuntos
Receptores Histamínicos H2/genética , Animais , Expressão Gênica , Coração/fisiologia , Frequência Cardíaca/genética , Humanos , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos , Volume Sistólico/genética
5.
PLoS One ; 14(2): e0211908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735526

RESUMO

Three artificially selected duck populations (AS), higher lean meat ratios (LTPD), higher fat ratios (FTPD) and higher quality meat (CMD), have been developed in China, providing excellent populations for investigation of artificial selection effects. However, the genetic signatures of artificial selection are unclear. In this study, we sequenced the genome sequences of these three artificially selected populations and their ancestral population (mallard, M). We then compared the genome sequences between AS and M and between LTPD and FTPD using integrated strategies such as anchoring scaffolds to pseudo-chromosomes, mutation detection, selective screening, GO analysis, qRT-PCR, and protein multiple sequences alignment to uncover genetic signatures of selection. We anchored duck scaffolds to pseudo-chromosomes and obtained 28 pseudo-chromosomes, accounting for 84% of duck genome in length. Totally 78 and 99 genes were found to be under selection between AS and M and between LTPD and FTPD. Genes under selection between AS and M mainly involved in pigmentation and heart rates, while genes under selection between LTPD and FTPD involved in muscle development and fat deposition. A heart rate regulator (HCN1), the strongest selected gene between AS and M, harbored a GC deletion in AS and displayed higher mRNA expression level in M than in AS. IGF2R, a regulator of skeletal muscle mass, was found to be under selection between FTPD and LTPD. We also found two nonsynonymous substitutions in IGF2R, which might lead to higher IGF2R mRNA expression level in FTPD than LTPD, indicating the two nonsynonymous substitutions might play a key role for the regulation of duck skeletal muscle mass. Taken together, these results of this study provide valuable insight for the genetic basis of duck artificial selection.


Assuntos
Proteínas Aviárias/genética , Composição Corporal/genética , Patos/genética , Genoma , Carne , Seleção Genética , Tecido Adiposo/metabolismo , Sequência de Aminoácidos , Animais , Proteínas Aviárias/metabolismo , Cruzamento/métodos , Mapeamento Cromossômico , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Frequência Cardíaca/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Masculino , Anotação de Sequência Molecular , Músculo Esquelético/metabolismo , Pigmentação/genética , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
6.
Arch Cardiovasc Dis ; 112(2): 124-134, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30600215

RESUMO

BACKGROUND: The P2Y13 purinergic receptor regulates hepatic high-density lipoprotein uptake and biliary sterol secretion; it acts downstream of the membrane ecto-F1-adenosine triphosphatase, which generates extracellular adenosine diphosphate that selectively activates P2Y13, resulting in high-density lipoprotein endocytosis. Previous studies have shown that the serum concentration of the F1-adenosine triphosphatase inhibitor inhibitory factor 1 is negatively associated with cardiovascular risk. AIM: To evaluate whether p2y13 genetic variants affect cardiovascular risk. METHODS: Direct sequencing of the p2y13 coding and flanking regions was performed in a subcohort of 168 men aged 45-74 years with stable coronary artery disease and 173 control subjects from the GENES study. The two most frequent mutations, rs3732757 and rs1466684, were genotyped in 767 patients with coronary artery disease and 789 control subjects, and their association with cardiovascular risk markers was analysed. RESULTS: Carriers of the rs3732757 261T and rs1466684 557G alleles represented 9% and 27.5% of the entire population, respectively. The allele frequencies were identical in patients with coronary artery disease and control subjects. The presence of 261T was associated with higher concentrations of plasma lipoprotein A-I and inhibitory factor 1, increased fat mass and a lower heart rate. Moreover, the proportion of patients with coronary artery disease with a pejorative systolic ankle-brachial index was lower in carriers of the 261T allele. In both populations, the 557G allele was associated with increased concentrations of lipoprotein(a), and an allele dose effect was observed. CONCLUSIONS: Two frequent p2y13 variants are associated with specific bioclinical markers of cardiovascular risk. Although neither one of these variants appears to be related to the development of atherosclerotic disease, they may modulate the risk of additional cardiovascular complications.


Assuntos
Adiposidade/genética , Doença da Artéria Coronariana/genética , Frequência Cardíaca/genética , Lipoproteína(a)/sangue , Polimorfismo de Nucleotídeo Único , Proteínas/análise , Receptores Purinérgicos P2/genética , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , França , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Fatores de Risco
7.
Dev Psychopathol ; 31(1): 293-307, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248020

RESUMO

Dysregulated physiological stress reactivity has been suggested to impact the development of children and adolescents with important health consequences throughout the life span. Both environmental adversity and genetic predispositions can lead to physiological imbalances in stress systems, which in turn lead to developmental differences. We investigated genetic and environmental contributions to autonomic nervous system reactivity to a psychosocial stressor. Furthermore, we tested whether these effects were consistent with the differential susceptibility framework. Composite measures of adverse life events combined with socioeconomic status were constructed. Effects of these adversity scores in interaction with a polygenic score summarizing six genetic variants, which were hypothesized to work as susceptibility factors, were tested on autonomic nervous system measures as indexed by heart rate and heart rate variability. Results showed that carriers of more genetic variants and exposed to high adversity manifested enhanced heart rate variability reactivity to a psychosocial stressor compared to carriers of fewer genetic variants. Conversely, the stress procedure elicited a more moderate response in these individuals compared to carriers of fewer variants when adversity was low.


Assuntos
Nível de Alerta/fisiologia , Sistema Nervoso Autônomo/fisiopatologia , Interação Gene-Ambiente , Estresse Psicológico/fisiopatologia , Adolescente , Nível de Alerta/genética , Criança , Feminino , Triagem de Portadores Genéticos , Predisposição Genética para Doença/genética , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Humanos , Acontecimentos que Mudam a Vida , Masculino , Herança Multifatorial/genética , Herança Multifatorial/fisiologia , Classe Social , Estresse Fisiológico , Estresse Psicológico/genética
8.
Circ Res ; 124(1): 66-78, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582453

RESUMO

RATIONALE: Short QT syndrome (SQT) is a rare but arrhythmogenic disorder featured by shortened ventricular repolarization and a propensity toward life-threatening ventricular arrhythmias and sudden cardiac death. OBJECTIVE: This study aimed to investigate the single-cell mechanism of SQT using patient-specific and gene-corrected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). METHODS AND RESULTS: One SQT patient carrying missense mutation T618I in potassium voltage-gated channel subfamily H member 2 ( KCNH2) was recruited as well as 2 healthy control subjects in this study. Control and SQT patient-specific iPSCs were generated from skin fibroblasts using nonintegrated Sendai virus. The KCNH2 T618I mutation was corrected by genome editing in SQT iPSC lines to generate isogenic controls. All iPSCs were differentiated into iPSC-CMs using monolayer-based differentiation protocol. SQT iPSC-CMs exhibited abnormal action potential phenotype featured by shortened action potential duration and increased beat-beat interval variability, when compared with control and gene-corrected iPSC-CMs. Furthermore, SQT iPSC-CMs showed KCNH2 gain-of-function with increased rapid delayed rectifying potassium current (IKr) density and enhanced membrane expression. Gene expression profiling of iPSC-CMs exhibited a differential cardiac ion-channel gene expression profile of SQT. Moreover, QTc of SQT patient and action potential durations of SQT iPSC-CMs were both normalized by quinidine, indicating that quinidine is beneficial to KCNH2 T618I of SQT. Importantly, shortened action potential duration phenotype observed in SQT iPSC-CMs was effectively rescued by a short-peptide scorpion toxin BmKKx2 with a mechanism of targeting KCNH2. CONCLUSIONS: We demonstrate that patient-specific and gene-corrected iPSC-CMs are able to recapitulate single-cell phenotype of SQT, which is caused by the gain-of-function mutation KCNH2 T618I. These findings will help elucidate the mechanisms underlying SQT and discover therapeutic drugs for treating the disease by using peptide toxins as lead compounds.


Assuntos
Potenciais de Ação/genética , Arritmias Cardíacas/genética , Canal de Potássio ERG1/genética , Mutação com Ganho de Função , Edição de Genes/métodos , Frequência Cardíaca/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação de Sentido Incorreto , Miócitos Cardíacos/metabolismo , Análise de Célula Única/métodos , Adulto , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Sistemas CRISPR-Cas , Estudos de Casos e Controles , Linhagem Celular , Linhagem da Célula , Canal de Potássio ERG1/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Tempo
9.
Nat Commun ; 9(1): 5054, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30498205

RESUMO

With the recent deluge of mega-biobank data, it is time to revisit what constitutes "replication" for genome-wide association studies. Many replication samples are unavailable or underpowered, therefore alternatives beyond strict statistical replication are needed until the required resources become available.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Bases de Dados Genéticas , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
10.
Circ Res ; 123(8): 953-963, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30355031

RESUMO

RATIONALE: Autosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia. OBJECTIVE: To determine if somatic in vivo genome editing using the CRISPR/Cas9 system delivered by adeno-associated viral (AAV) vectors could correct catecholaminergic polymorphic ventricular tachycardia arrhythmias in mice heterozygous for RyR2 mutation R176Q (R176Q/+). METHODS AND RESULTS: Guide RNAs were designed to specifically disrupt the R176Q allele in the R176Q/+ mice using the SaCas9 ( Staphylococcus aureus Cas9) genome editing system. AAV serotype 9 was used to deliver Cas9 and guide RNA to neonatal mice by single subcutaneous injection at postnatal day 10. Strikingly, none of the R176Q/+ mice treated with AAV-CRISPR developed arrhythmias, compared with 71% of R176Q/+ mice receiving control AAV serotype 9. Total Ryr2 mRNA and protein levels were significantly reduced in R176Q/+ mice, but not in wild-type littermates. Targeted deep sequencing confirmed successful and highly specific editing of the disease-causing R176Q allele. No detectable off-target mutagenesis was observed in the wild-type Ryr2 allele or the predicted putative off-target site, confirming high specificity for SaCas9 in vivo. In addition, confocal imaging revealed that gene editing normalized the enhanced Ca2+ spark frequency observed in untreated R176Q/+ mice without affecting systolic Ca2+ transients. CONCLUSIONS: AAV serotype 9-based delivery of the SaCas9 system can efficiently disrupt a disease-causing allele in cardiomyocytes in vivo. This work highlights the potential of somatic genome editing approaches for the treatment of lethal autosomal-dominant inherited cardiac disorders, such as catecholaminergic polymorphic ventricular tachycardia.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Terapia Genética/métodos , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/terapia , Potenciais de Ação/genética , Animais , Proteína 9 Associada à CRISPR/genética , Sinalização do Cálcio/genética , Dependovirus/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Vetores Genéticos , Frequência Cardíaca/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , RNA Guia/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia
11.
Trans Am Clin Climatol Assoc ; 129: 183-184, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30166713

RESUMO

Inherited conditions that lead to cardiac arrhythmias and sudden cardiac death remain an important cause of morbidity and mortality. Identifying the genes responsible for these rare conditions can provide insights into the more common and heritable forms of sudden cardiac death seen in patients with structural heart disease. We and others have used candidate gene approaches and positional cloning in large families to show that mutations in ion channels and ion channel related proteins cause familial arrhythmia syndromes including long QT and Brugada syndromes. The genes responsible for many familial arrhythmia syndromes and the vast majority of the predisposition to common arrhythmias remain unknown. Using whole exome sequencing in families with Brugada syndrome and idiopathic ventricular fibrillation, we now seek to identify mutations in genes previously not thought to play a significant role in the heart.


Assuntos
Síndrome de Brugada/genética , Análise Mutacional de DNA/métodos , Morte Súbita Cardíaca/etiologia , Frequência Cardíaca/genética , Mutação , Fibrilação Ventricular/genética , Sequenciamento Completo do Exoma/métodos , Síndrome de Brugada/complicações , Síndrome de Brugada/mortalidade , Síndrome de Brugada/fisiopatologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Prognóstico , Fatores de Risco , Fibrilação Ventricular/complicações , Fibrilação Ventricular/mortalidade , Fibrilação Ventricular/fisiopatologia
12.
J Diabetes Res ; 2018: 8454078, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30246030

RESUMO

Background: In vivo experiments in Goto-Kakizaki (GK) type 2 diabetic rats have demonstrated reductions in heart rate from a young age. The expression of genes encoding more than 70 proteins that are associated with the generation and conduction of electrical activity in the GK sinoatrial node (SAN) have been evaluated to further clarify the molecular basis of the low heart rate. Materials and Methods: Heart rate and expression of genes were evaluated with an extracellular electrode and real-time RT-PCR, respectively. Rats aged 12-13 months were employed in these experiments. Results: Isolated spontaneous heart rate was reduced in GK heart (161 ± 12 bpm) compared to controls (229 ± 11 bpm). There were many differences in expression of mRNA, and some of these differences were of particular interest. Compared to control SAN, expression of some genes were downregulated in GK-SAN: gap junction, Gja1 (Cx43), Gja5 (Cx40), Gjc1 (Cx45), and Gjd3 (Cx31.9); cell membrane transport, Trpc1 (TRPC1) and Trpc6 (TRPC6); hyperpolarization-activated cyclic nucleotide-gated channels, Hcn1 (HCN1) and Hcn4 (HCN4); calcium channels, Cacna1d (Cav1.3), Cacna1g (Cav3.1), Cacna1h (Cav3.2), Cacna2d1 (Cavα2δ1), Cacna2d3 (Cavα2δ3), and Cacng4 (Cav γ 4); and potassium channels, Kcna2 (Kv1.2), Kcna4 (Kv1.4), Kcna5 (Kv1.5), Kcnb1 (Kv2.1), Kcnd3 (Kv4.3), Kcnj2 (Kir2.1), Kcnk1 (TWIK1), Kcnk5 (K2P5.1), Kcnk6 (TWIK2), and Kcnn2 (SK2) whilst others were upregulated in GK-SAN: Ryr2 (RYR2) and Nppb (BNP). Conclusions: This study provides new insight into the changing expression of genes in the sinoatrial node of diabetic heart.


Assuntos
Arritmias Cardíacas/genética , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/genética , RNA Mensageiro/genética , Nó Sinoatrial/metabolismo , Potenciais de Ação , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Frequência Cardíaca/genética , Preparação de Coração Isolado , Masculino , RNA Mensageiro/metabolismo , Ratos Wistar , Nó Sinoatrial/fisiopatologia
13.
Pregnancy Hypertens ; 13: 214-217, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30177054

RESUMO

OBJECTIVES: SNP rs2200733 located near PITX2 gene is associated with the risk of atrial fibrillation. Preeclamptic women are at increased risk of developing cardiovascular disease like atrial fibrillation. Whether this translates into an association between SNP rs2200733 and preeclampsia is not known. Therefore, we determined the association of SNP rs2200733 (C/T) with the risk of preeclampsia. STUDY DESIGN: A hospital based prospective case-control study involving 585 pregnant women of whom 285 were preeclamptic and 300 were normotensive. SNP rs2200733 was genotyped by PCR-RFLP method. MAIN OUTCOME MEASURES: Statistical significance of the difference in the minor allele frequency between case and control groups was determined by Fisher's exact test. RESULTS: Minor allele frequency was 21.4% among preeclamptic pregnant women and 13.7% among normotensive pregnant women (P = 0.00064; odds ratio = 1.72 (0.95 CI: 1.23-2.41). The measures of association were heterogeneous when compared after categorisation of the preeclamptic group into clinical sub-groups. The association was not significant with the eclampsia sub-group (P = 0.39) but relatively higher with the sub-group not superimposed by eclampsia (P = 0.0000048; odds ratio = 2.10 [0.95CI: 1.50-2.92]). Furthermore, the association was relatively higher with the sub-group involving intrauterine growth retardation and intrauterine death (P = 0.00017; odds ratio = 2.89 (0.95CI: 1.65-4.94)]. CONCLUSIONS: Minor allele of SNP rs2200733 is associated with the risk of preeclampsia. SNP rs220073 may represent a common risk factor that predispose women to develop both preeclampsia during pregnancy and cardiovascular disease later on.


Assuntos
Fibrilação Atrial/genética , Proteínas de Homeodomínio/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Fatores de Transcrição/genética , Adulto , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Pressão Sanguínea/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Frequência Cardíaca/genética , Humanos , Fenótipo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
14.
Am J Physiol Heart Circ Physiol ; 315(5): H1250-H1257, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30118344

RESUMO

Mutations in voltage-gated Na+ channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage-gated Na+ channel (Nav)1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel. We also reported that voltage-gated Na+ channels associate as dimers with coupled gating properties. Here, we hypothesized that the dominant negative effect of mutant Na+ channels could also occur through coupled gating. This was tested using cell surface biotinylation and single channel recordings to measure the gating probability and coupled gating of the dimers. As previously reported, coexpression of Nav1.5-L325R with WT channels led to a dominant negative effect, as reflected by a 75% reduction in current density. Surprisingly, cell surface biotinylation showed that Nav1.5-L325R mutant is capable of trafficking, with 40% of Nav1.5-L325R reaching the cell surface when expressed alone. Importantly, even though a dominant negative effect on the Na+ current is observed when WT and Nav1.5-L325R are expressed together, the total Nav channel cell surface expression was not significantly altered compared with WT channels alone. Thus, the trafficking deficiency could not explain the 75% decrease in inward Na+ current. Interestingly, single channel recordings showed that Nav1.5-L325R exerted a dominant negative effect on the WT channel at the gating level. Both coupled gating and gating probability of WT:L325R dimers were drastically impaired. We conclude that dominant negative suppression exerted by Nav1.5 mutants can also be caused by impairing the WT gating probability, a mechanism resulting from the dimerization and coupled gating of voltage-gated Na+ channel α-subunits. NEW & NOTEWORTHY The presence of dominant negative mutations in the Na+ channel gene leading to Brugada syndrome was supported by our recent findings that Na+ channel α-subunits form dimers. Up until now, the dominant negative effect was thought to be caused by the interaction of the wild-type Na+ channel with trafficking-deficient mutant channels. However, the present study demonstrates that coupled gating of voltage-gated Na+ channels can also be responsible for the dominant negative effect leading to arrhythmias.


Assuntos
Ativação do Canal Iônico/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Sódio/metabolismo , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Células HEK293 , Frequência Cardíaca/genética , Humanos , Cadeias de Markov , Potenciais da Membrana , Modelos Biológicos , Multimerização Proteica , Transporte Proteico , Fatores de Tempo
15.
Behav Genet ; 48(5): 386-396, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29995284

RESUMO

Reduced heart rate variability (HRV) is associated with cardiac morbidity, mortality, and negative psychopathology. Most research concerning genetic influences on HRV has focused on adult populations, with fewer studies investigating the developmental period of adolescence and emerging adulthood. The current study estimated the genetic and environmental contributions to resting HRV in a sample of twins using various HRV time domain metrics to assess autonomic function across two different time measurement intervals (2.5- and 10-min). Five metrics of resting HRV [mean interbeat interval (IBI), the standard deviation of normal IBIs (SDNN), root square mean of successive differences between IBIs (RMSSD), cardiac vagal index (CVI), and cardiac sympathetic index (CSI)] were assessed in 421 twin pairs aged 14-20 during a baseline electrocardiogram. This was done for four successive 2.5-min intervals as well as the overall 10-min interval. Heritability (h2) appeared consistent across intervals within each metric with the following estimates (collapsed across time intervals): mean IBI (h2 = 0.36-0.46), SDNN (h2 = 0.23-0.30), RMSSD (h2 = 0.36-0.39), CVI (h2 = 0.37-0.42), CSI (h2 = 0.33-0.46). Beyond additive genetic contributions, unique environment also was an important influence on HRV. Within each metric, a multivariate Cholesky decomposition further revealed evidence of genetic stability across the four successive 2.5-min intervals. The same models showed evidence for both genetic and environmental stability with some environmental attenuation and innovation. All measures of HRV were moderately heritable across time, with further analyses revealing consistent patterns of genetic and environmental influences over time. This study confirms that in an adolescent sample, the time interval used (2.5- vs. 10-min) to measure HRV time domain metrics does not affect the relative proportions of genetic and environmental influences.


Assuntos
Frequência Cardíaca/genética , Descanso , Adolescente , Feminino , Humanos , Padrões de Herança/genética , Masculino , Modelos Genéticos , Análise Multivariada , Fatores de Tempo , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
16.
Free Radic Biol Med ; 126: 113-121, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031863

RESUMO

Oral reduction of nitrate to nitrite is dependent on the oral microbiome and is the first step of an alternative mammalian pathway to produce nitric oxide in humans. Preliminary evidence suggests important sex differences in this pathway. We prospectively investigated sex-differences following inorganic nitrate supplementation on nitrate/nitrite levels and vascular function, and separately examined sex differences in oral nitrate reduction, and oral microbiota by 16S rRNA profiling. At baseline, females exhibit higher nitrite levels in all biological matrices despite similar nitrate levels to males. Following inorganic nitrate supplementation, plasma nitrite was increased to a significantly greater extent in females than in males and pulse wave velocity was only reduced in females. Females exhibited higher oral bacterial nitrate-reducing activity at baseline and after nitrate supplementation. Despite these differences, there were no differences in the composition of either the total salivary microbiota or those oral taxa with nitrate reductase genes. Our results demonstrate that females have augmented oral nitrate reduction that contributes to higher nitrite levels at baseline and also after inorganic nitrate supplementation, however this was not associated with differences in microbial composition (clinicaltrials.gov: NCT01583803).


Assuntos
Bactérias/metabolismo , Microbiota/genética , Óxido Nítrico/genética , Nitritos/metabolismo , Adolescente , Adulto , Bactérias/genética , Feminino , Frequência Cardíaca/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Boca/metabolismo , Boca/microbiologia , Nitratos/metabolismo , Óxidos de Nitrogênio/metabolismo , RNA Ribossômico 16S/genética , Saliva/metabolismo , Saliva/microbiologia , Caracteres Sexuais , Adulto Jovem
17.
Psychoneuroendocrinology ; 97: 28-36, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30005279

RESUMO

OBJECTIVE: To examine the impact of polymorphic variation in the solute carrier family 5 member 7 (SLC5A7) gene on autonomic nervous system (ANS) reactivity indexed by respiratory sinus arrhythmia (RSA) and heart rate (HR) in infants during a dyadic stressor, as well as maternal report of infant self-regulation. Given evidence of race differences in older individuals, race was specifically examined. METHODS: RSA and HR were collected from 111 infants during the still-face paradigm (SFP). Mothers completed the Infant Behavior Questionnaire-Revised short-form. Multi-level mixed effects models examined the impact of SLC5A7 genotype on RSA and HR across the SFP. Linear models tested the influence of genotype on the relation between RSA, HR, and maternal report of infant self-regulation. RESULTS: SLC5A7 genotype significantly predicted RSA stress responsivity (ß = -0.023; p = 0.028) and HR stress responsivity (ß = 0.004; p = 0.002). T-allele carriers exhibited RSA suppression and HR acceleration in response to stress while G/G homozygotes did not suppress RSA and exhibited less HR acceleration. All infants exhibited modest RSA augmentation and HR deceleration during recovery. Race-stratified analyses revealed that White T-allele carriers drove the overall results for both RSA (ß = -0.044; p = 0.007) and HR (ß = 0.006; p = 0.008) with no relation between SLC5A7 genotype and RSA or HR in Black infants. Maternal report of infant orienting/regulation was predicted by the interaction of SLC5A7 genotype and both RSA recovery (ß = 0.359; p = 0.001) and HR recovery (ß = -1.659; p = 0.020). RSA augmentation and HR deceleration during recovery were associated with higher maternal reports of self-regulation among T-allele carriers, a finding again primarily driven by White infants. CONCLUSIONS: Early in development, genetic contributions to ANS are evident and predict maternal report of infant self-regulation within White infants, consistent with prior literature. The lack of associations in Black infants suggest that race differences in physiological reactivity and self-regulation are emerging during the first year of life potentially providing early evidence of disparities in health risk trajectories.


Assuntos
Frequência Cardíaca/genética , Arritmia Sinusal Respiratória/genética , Simportadores/genética , Adulto , Afro-Americanos , Alelos , Sistema Nervoso Autônomo , Biomarcadores , Desenvolvimento Infantil , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene/genética , Humanos , Lactente , Comportamento do Lactente/psicologia , Recém-Nascido , Masculino , Relações Mãe-Filho , Mães , Polimorfismo de Nucleotídeo Único/genética , Fatores Raciais , Estresse Psicológico/genética , Simportadores/metabolismo , Temperamento
18.
Eur J Appl Physiol ; 118(10): 2097-2110, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30006671

RESUMO

INTRODUCTION: Physical health and function depend upon both genetic inheritance and environmental factors (e.g., exercise training). PURPOSE: To enhance the understanding of heritability/adaptability, we explored the skeletal muscle health and physiological performance of monozygotic (MZ) twins with > 30 years of chronic endurance training vs. no specific/consistent exercise. METHODS: One pair of male MZ twins (age = 52 years; Trained Twin, TT; Untrained Twin, UT) underwent analyses of: (1) anthropometric characteristics and blood profiles, (2) markers of cardiovascular and pulmonary health, and (3) skeletal muscle size, strength, and power and molecular markers of muscle health. RESULTS: This case study represents the most comprehensive physiological comparison of MZ twins with this length and magnitude of differing exercise history. TT exhibited: (1) lower body mass, body fat%, resting heart rate, blood pressure, cholesterol, triglycerides, and plasma glucose, (2) greater relative cycling power, anaerobic endurance, and aerobic capacity (VO2max), but lower muscle size/strength and poorer muscle quality, (3) more MHC I (slow-twitch) and fewer MHC IIa (fast-twitch) fibers, (4) greater AMPK protein expression, and (5) greater PAX7, IGF1Ec, IGF1Ea, and FN14 mRNA expression than UT. CONCLUSIONS: Several measured differences are the largest reported between MZ twins (TT expressed 55% more MHC I fibers, 12.4 ml/kg/min greater VO2max, and 8.6% lower body fat% vs. UT). These data collectively (a) support utilizing chronic endurance training to improve body composition and cardiovascular health and (b) suggest the cardiovascular and skeletal muscle systems exhibit greater plasticity than previously thought, further highlighting the importance of studying MZ twins with large (long-term) differences in exposomes.


Assuntos
Exercício Físico/fisiologia , Músculo Esquelético/fisiologia , Gêmeos Monozigóticos/genética , Proteínas Quinases Ativadas por AMP/genética , Adaptação Fisiológica/genética , Adaptação Fisiológica/fisiologia , Glicemia/genética , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Colesterol/sangue , Colesterol/genética , Hábitos , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Triglicerídeos/genética
19.
Circ Arrhythm Electrophysiol ; 11(7): e006035, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29925535

RESUMO

BACKGROUND: Cardiac repolarization abnormalities in drug-induced and genetic long-QT syndrome may lead to afterdepolarizations and life-threatening ventricular arrhythmias. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) should help to overcome the limitations of animal models based on species differences in repolarization reserve. Here, we compared head-to-head the contribution of IKs (long QT1) and IKr (long QT2) on action potentials (APs) in human left ventricular (LV) tissue and hiPSC-CM-derived engineered heart tissue (EHT). METHODS: APs were measured with sharp microelectrodes in EHT from 3 different control hiPSC-CM lines and in tissue preparations from failing LV. RESULTS: EHT from hiPSC-CMs showed spontaneous diastolic depolarization and AP generation that were sensitive to low concentrations of ivabradine. IKr block by E-4031 prolonged AP duration at 90% repolarization with similar half-effective concentration in EHT and LV but larger effect size in EHT (+281 versus +110 ms in LV). Although IKr block alone evoked early afterdepolarizations and triggered activity in 50% of EHTs, slow pacing, reduced extracellular K+, and blocking of IKr, IKs, and IK1 were necessary to induce early afterdepolarizations in LV. In accordance with their clinical safety, moxifloxacin and verapamil did not induce early afterdepolarizations in EHT. In both EHT and LV, IKs block by HMR-1556 prolonged AP duration at 90% repolarization slightly in the combined presence of E-4031 and isoprenaline. CONCLUSIONS: EHT from hiPSC-CMs shows a lower repolarization reserve than human LV working myocardium and could thereby serve as a sensitive and specific human-based model for repolarization studies and arrhythmia, similar to Purkinje fibers. In both human LV and EHT, IKs only contributed to repolarization under adrenergic stimulation.


Assuntos
Potenciais de Ação , Arritmias Cardíacas/induzido quimicamente , Bioensaio , Frequência Cardíaca , Ventrículos do Coração/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Síndrome do QT Longo/genética , Síndrome de Romano-Ward/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Linhagem Celular , Simulação por Computador , Canal de Potássio ERG1/genética , Canal de Potássio ERG1/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/genética , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ1/metabolismo , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Modelos Cardiovasculares , Fenótipo , Bloqueadores dos Canais de Potássio/farmacologia , Medição de Risco , Síndrome de Romano-Ward/tratamento farmacológico , Síndrome de Romano-Ward/metabolismo , Síndrome de Romano-Ward/fisiopatologia , Fatores de Tempo
20.
Epilepsia ; 59(7): 1372-1380, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29873813

RESUMO

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a tragic and devastating event for which the underlying pathophysiology remains poorly understood; this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes. METHODS: We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep, from 80 patients with drug-resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non-SCN drug-resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non-SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios. RESULTS: The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep-to-awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non-SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group. SIGNIFICANCE: These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study; HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.


Assuntos
Biomarcadores , Morte Súbita/etiologia , Epilepsia/fisiopatologia , Frequência Cardíaca/fisiologia , Risco , Adolescente , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Epilepsia/genética , Feminino , Frequência Cardíaca/genética , Humanos , Lactente , Masculino , Estudos Retrospectivos , Sono/fisiologia , Canais de Sódio/genética , Vigília/fisiologia , Adulto Jovem
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