Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development.

Flap endonuclease 1 (FEN1) phosphorylation is proposed to regulate the action of FEN1 in DNA repair as well as Okazaki fragment maturation. However, the biologic significance of FEN1 phosphorylation in response to DNA damage remains unknown. Here, we report an in vivo role for FEN1 phosphorylation, using a mouse line carrying S187A FEN1, which abolishes FEN1 phosphorylation. Although S187A mouse embryonic fibroblast cells showed normal proliferation under low oxygen levels (2%), the mutant cells accumulated oxidative DNA damage, activated DNA damage checkpoints, and showed G1-phase arrest at atmospheric oxygen levels (21%). This suggests an essential role for FEN1 phosphorylation in repairing oxygen-induced DNA damage and maintaining proper cell cycle progression. Consistently, the mutant cardiomyocytes showed G1-phase arrest due to activation of the p53-mediated DNA damage response at the neonatal stage, which reduces the proliferation potential of the cardiomyocytes and impairs heart development. Nearly 50% of newborns with the S187A mutant died in the first week due to failure to undergo the peroxisome proliferator-activated receptor signaling-dependent switch from glycolysis to fatty acid oxidation. The adult mutant mice developed dilated hearts and showed significantly shorter life spans. Altogether, our results reveal an important role of FEN1 phosphorylation to counteract oxygen-induced stress in the heart during the fetal-to-neonatal transition.-Zhou, L., Dai, H., Wu, J., Zhou, M., Yuan, H., Du, J., Yang, L., Wu, X., Xu, H., Hua, Y., Xu, J., Zheng, L., Shen, B. Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development.

Frecuencia de lesiones coronarias epicárdicas en pacientes con cardiopatía dilatada en un Departamento de Cardiología en el periodo 2015 - 2021 / Frequency of epicardial coronary lesions in patients with Dilated Heart Disease in a Department of Cardiology in the period from 2015 to 2021

RESUMEN Introducción: la cardiopatía dilatada definida como la dilatación de cavidades cardiacas de múltiples etiologías tiene una prevalencia en adultos de alrededor de 1/2.500 individuos. La ecocardiografía transtorácica determina la dilatación de cavidades y evalúa la función ventricular mientras que la cinecoronariografía permite identificar la etiología principalmente isquémica por afección de arterias coronarias epicárdicas. La utilización de la cinecoronariografía como primera línea para el diagnóstico etiológico, implica riesgos propios de un método invasivo con un alto costo en recursos económicos, por lo cual es imperioso determinar el posible resultado de dicho procedimiento. Objetivo: determinar la frecuencia de lesiones coronarias epicárdicas en pacientes con Cardiopatía Dilatada en un Departamento de Cardiología en el periodo del 2015 ­ 2021. Metodología: estudio observacional, descriptivo, retrospectivo y de corte transversal con muestreo no probabilístico por conveniencia, mediante la revisión en la base de datos en un Departamento de Cardiología. Resultados: este estudio incluyó a 88 pacientes, con disnea en clase funcional II-IV de la NYHA y cardiopatía dilatada por ecocardiografía, de etiología no filiada. De éste grupo, 66 % eran varones y 34 % mujeres, la media de edad fue de 56 ± 11,19 años. Al ser sometidos a cinecoronariografía diagnostica, se constató que el 23 % presentó lesiones coronarias epicárdicas, siendo la más frecuente la lesión de un vaso (55 %), predominando el sexo masculino en aquellos con o sin lesiones coronarias epicárdicas. Conclusiones: la frecuencia de lesiones coronarias epicárdicas en pacientes con cardiopatía dilatada, es baja.

ABSTRACT Introduction: dilated heart disease defined as the dilation of cardiac cavities of multiple etiologies has a prevalence in adults of around 1/2.500 individuals. Transthoracic echocardiography determines chamber dilation and evaluates ventricular function, while coronary angiography can identify the mainly ischemic etiology due to involvement of the epicardial coronary arteries. The use of coronary angiography as the first line for the etiological diagnosis implies risks of an invasive method with a high cost in economic resources, for which it is imperative to determine the possible result of said procedure. Objective: to determine the frequency of epicardial coronary lesions in patients with Dilated Heart Disease in a Departmento de Cardiología in the period 2015-2021. Methodology: observational, descriptive, retrospective and cross-sectional study with non-probabilistic convenience sampling, by reviewing the database in a Departmento de Cardiología. Results: this study included 88 patients, with dyspnea in NYHA functional class II-IV and dilated heart disease by echocardiography, of unknown etiology. Out of this group, 66% were men and 34 % women, the mean age was 56 ± 11.19 years. When undergoing diagnostic cinecoronariography, it was found that 23 % had epicardial coronary lesions, the most frequent being a lesion of a vessel (55 %), with the male sex predominating in those with or without epicardial coronary lesions. Conclusions: the frequency of epicardial coronary lesions in patients with dilated heart disease is low.

Uso de células-tronco no tratamento de pacientes com miocardiopatia dilatada de diferentes etiologias, associada à ressincronização cardíaca artificial: [carta ao editor] / Stem cell to treat heart disease in association with artificial cardiac ressyncronization: [letter to the editor]

In spite of the development of pharmacological strategies, technology and more sophisticated surgical alternatives, incidences of death from cardiopathies remains high throughout the world, in particular in relation to dilated heart disease. Many of these patients benefit from recent strategies of early myocardial perfusion which significantly reduces mortality rates; even so past-infarction heart failure is common. Recent studies have shown that the infusion of autologous stem cells is a possible treatment to reverse ventricular dysfunction. However, frequently there is an associated electrical conduction defect. Thus, an infusion of stem cells may produce a mechanical correction with heart resynchronization correcting the electrical conduction defect thereby improving the left ventricle ejection fraction. Our institution has been combining stem cell transplantation with resynchronization and, when necessary, cardiofibrilation, to treat these patients giving improvements in the Functional Class, ejection fraction and left ventricle and right ventricle-left ventricle synchrony.