ELIDA ADALGISA NERI

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Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina

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Autor: SANTOS-MIRANDA, Artur ×

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  • article 7 Citação(ões) na Scopus
    The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells
    (2022) SANTOS-MIRANDA, Artur; JOVIANO-SANTOS, V. Julliane; CRUZ-NASCIMENTO, Taynara; NERI, Elida Adalgisa; SOUZA, Diego Santos; MARQUES, Leisiane Pereira; KRIEGER, Jose E.; ROMAN-CAMPOS, Danilo
    Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is widely used in agriculture and its use has experienced a tremendous increase in the last decade. The long-term exposure of humans to this pesticide is a real threat because it is stable in water and soil. The association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity is evident, however, acute toxicological studies to reveal the toxicity of TEB are limited. This research paper addressed the acute exposure of TEB in murine hearts, cardiomyocytes, and human cardiomyocytes derived from an induced pluripotent stem cell (hiPSC-CMs), spelling out TEB's impact on electromechanical properties of the cardiac tissue. In ex vivo experiments, TEB dose dependently, caused significant electrocardiogram (ECG) remodeling with prolonged PR and QTc interval duration. The TEB was also able to change the action potential waveform in murine cardiomyocytes and hiPSC-CMs. These effects were associated with the ability of the compound to block the L-type calcium current (IC50 = 33.2 +/- 7.4 mu mol.l(-1)) and total outward potassium current (IC50 = 5.7 +/- 1.5 mu mol.l(-1)). TEB also increased the sodium/calcium exchanger current in its forward and reverse modes. Additionally, sarcomere shortening and calcium transient in isolated cardiomyocytes were enhanced when cells were exposed to TEB at 30 mu mol.l(-1). Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electrocontractile properties and triggers the appearance of ECG abnormalities.
  • conferenceObject
    Tebuconazole fungicide interacts with human Nav1.5 channels and alters the cellular excitability of cardiomyocytes derived from human induced pluripotent stem cells
    (2022) MARQUES, Leisiane; SANTOS-MIRANDA, Artur; JOVIANO-SANTOS, Julliane; NERI, Elida A.; SARMENTO, Jaqueline O.; KRIEGER, Jose Eduardo; CAMPOS, Danilo Roman
  • article 10 Citação(ões) na Scopus
    NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro
    (2020) SILVA, Agatha Ribeiro da; NERI, Elide A.; TURACA, Lauro Thiago; DARIOLLI, Rafael; FONSECA-ALANIZ, Miriam H.; SANTOS-MIRANDA, Artur; ROMAN-CAMPOS, Danilo; VENTURINI, Gabriela; KRIEGER, Jose E.
    Cardiac fibroblasts are present throughout the myocardium and are enriched in the microenvironment surrounding the ventricular conduction system (VCS). Several forms of arrhythmias are linked to VCS abnormalities, but it is still unclear whether VCS malformations are cardiomyocyte autonomous or could be linked to crosstalk between different cell types. We reasoned that fibroblasts influence cardiomyocyte specialization in VCS cells. We developed 2D and 3D culture models of neonatal rat cardiac cells to assess the influence of cardiac fibroblasts on cardiomyocytes. Cardiomyocytes adjacent to cardiac fibroblasts showed a two-fold increase in expression of VCS markers (NAV1.5 and CONTACTIN 2) and calcium transient duration, displaying a Purkinje-like profile. Fibroblast-conditioned media (fCM) was sufficient to activate VCS-related genes (Irx3, Scn5a, Connexin 40) and to induce action potential prolongation, a hallmark of Purkinge phenotype. fCM-mediated response seemed to be spatially-dependent as cardiomyocyte organoids treated with fCM had increased expression of connexin 40 and NAV1.5 primarily on its outer surface. Finally, NOTCH1 activation in both cardiomyocytes and fibroblasts was required for connexin 40 up-regulation (a proxy of VCS phenotype). Altogether, we provide evidence that cardiac fibroblasts influence cardiomyocyte specialization into VCS-like cells via NOTCH1 signaling in vitro.