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1.
JACC Basic Transl Sci ; 8(2): 109-120, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36124009

RESUMO

COVID-19 is associated with serious cardiovascular complications, with incompletely understood mechanism(s). Pericytes have key functions in supporting endothelial cells and maintaining vascular integrity. We demonstrate that human cardiac pericytes are permissive to SARS-CoV-2 infection in organotypic slice and primary cell cultures. Viral entry into pericytes is mediated by endosomal proteases, and infection leads to up-regulation of inflammatory markers, vasoactive mediators, and nuclear factor kappa-B-dependent cell death. Furthermore, we present evidence of cardiac pericyte infection in COVID-19 myocarditis patients. These data demonstrate that human cardiac pericytes are susceptible to SARS-CoV-2 infection and suggest a role for pericyte infection in COVID-19.

2.
JACC Basic Transl Sci ; 7(10): 1001-1017, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36337924

RESUMO

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered.

3.
JCI Insight ; 5(18)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32841220

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a murine genetic model is sufficient to increase ploidy in both atrial chambers. Notch activation within LA CMs generated a transcriptomic fingerprint resembling AF, with dysregulation of transcription factor and ion channel genes, including Pitx2, Tbx5, Kcnh2, Kcnq1, and Kcnip2. Notch activation also produced distinct cellular electrophysiologic responses in LA versus right atrial CMs, prolonging the action potential duration (APD) without altering the upstroke velocity in the left atrium and reducing the maximal upstroke velocity without altering the APD in the right atrium. Our results support a shared human/murine model of increased Notch pathway activity predisposing to AF.


Assuntos
Potenciais de Ação , Fibrilação Atrial/patologia , Biomarcadores/metabolismo , Regulação da Expressão Gênica , Átrios do Coração/patologia , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/patologia , Animais , Fibrilação Atrial/genética , Átrios do Coração/metabolismo , Insuficiência Cardíaca/genética , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transcriptoma
4.
J Mol Cell Cardiol ; 123: 92-107, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30193957

RESUMO

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology.


Assuntos
Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores , Biologia Computacional/métodos , Simulação por Computador , Suscetibilidade a Doenças , Eletrocardiografia , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genótipo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Imuno-Histoquímica , Mutação , Miócitos Cardíacos/metabolismo , Imagem Óptica , Fenótipo , Ligação Proteica , Proteínas Repressoras/metabolismo , Proteínas Wnt/genética , beta Catenina
5.
J Cardiovasc Dev Dis ; 5(1)2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29517992

RESUMO

The left and right ventricles of the four-chambered heart have distinct developmental origins and functions. Chamber-specific developmental programming underlies the differential gene expression of ion channel subunits regulating cardiac electrophysiology that persists into adulthood. Here, we discuss regional specific electrical responses to genetic mutations and cardiac stressors, their clinical correlations, and describe many of the multi-scale techniques commonly used to analyze electrophysiological regional heterogeneity.

6.
Channels (Austin) ; 11(6): 517-533, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-28837385

RESUMO

Shortly after cardiac Na+ channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na+ current, INa, and allowing the cell membrane to repolarize. A very limited number of Na+ channels that do not inactivate carry a persistent INa, or late INa. While late INa is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late INa would be best modeled with a "feet-on-the-door" approach where multiple channel components participate in determining inactivation and late INa. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late INa.


Assuntos
Modelos Biológicos , Miócitos Cardíacos/metabolismo , Canais de Sódio/metabolismo , Animais , Humanos
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