Silencing of epidermal growth factor receptor reduces Na+/H+ exchanger 1 activity and hypertensive cardiac hypertrophy

Brea, María Soledad; Díaz, Romina Gisel; Escudero, Daiana Sabrina; Zavala, Maite; Portiansky, Enrique Leo; Villa‐Abrille, María C.; Caldiz, Claudia Irma; Pérez, Néstor Gustavo; Morgan, Patricio E.

doi:10.1016/j.bcp.2019.113667

Cited by 5 publications

(3 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In vitro experiments indicate that EGFR activation promotes α 1-adrenergic receptor- and angiotensin II-induced cardiac hypertrophy [ 13 , 17 ]. Results of in vivo experiments also indicated that EGFR activation advances hypertensive cardiac hypertrophy in angiotensin II-induced hypertensive rats and SHRs [ 18 , 19 ], in agreement with our present findings that EGFR inhibition inhibited hypertensive cardiac hypertrophy in SHRs. Accordingly, EGFR activation is required in hypertensive cardiac hypertrophy.…”

Section: Discussionsupporting

confidence: 91%

Inhibition of the ROS-EGFR Pathway Mediates the Protective Action of Nox1/4 Inhibitor GKT137831 against Hypertensive Cardiac Hypertrophy via Suppressing Cardiac Inflammation and Activation of Akt and ERK1/2

Zeng

Yan

Yang

et al. 2020

Mediators of Inflammation

View full text Add to dashboard Cite

Oxidative stress, inflammation, and hypertension constitute a self-perpetuating vicious circle to exacerbate hypertension and subsequent hypertensive cardiac hypertrophy. NADPH oxidase (Nox) 1/4 inhibitor GKT137831 alleviates hypertensive cardiac hypertrophy in models of secondary hypertension; however, it remains unclear about its effect on hypertensive cardiac hypertrophy in models of essential hypertension. This study is aimed at determining the beneficial role of GKT137831 in hypertensive cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and its mechanisms of action. Treating with GKT137831 prevented cardiac hypertrophy in SHRs. Likewise, decreasing production of reactive oxygen species (ROS) with GKT137831 reduced epidermal growth factor receptor (EGFR) activity in the left ventricle of SHRs. Additionally, EGFR inhibition also reduced ROS production in the left ventricle and blunted hypertensive cardiac hypertrophy in SHRs. Moreover, inhibition of the ROS-EGFR pathway with Nox1/4 inhibitor GKT137831 or selective EGFR inhibitor AG1478 reduced protein and mRNA levels of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), as well as the activities of Akt and extracellular signal-regulated kinase (ERK) 1/2 in the left ventricle of SHRs. In summary, GKT137831 prevents hypertensive cardiac hypertrophy in SHRs, Nox-deprived ROS regulated EGFR activation through positive feedback in the hypertrophic myocardium, and inhibition of the ROS-EGFR pathway mediates the protective role of GKT137831 in hypertensive cardiac hypertrophy via repressing cardiac inflammation and activation of Akt and ERK1/2. This research will provide additional details for GKT137831 to prevent hypertensive cardiac hypertrophy.

show abstract

Section: Discussionsupporting

confidence: 91%

Inhibition of the ROS-EGFR Pathway Mediates the Protective Action of Nox1/4 Inhibitor GKT137831 against Hypertensive Cardiac Hypertrophy via Suppressing Cardiac Inflammation and Activation of Akt and ERK1/2

Zeng

Yan

Yang

et al. 2020

Mediators of Inflammation

View full text Add to dashboard Cite

show abstract

“…Cardiac ion channel complexes form the basis for excitation contraction coupling including calcium-induced calcium release and mechanical contraction and while ion channel dysregulation has been reported in cardiac hypertrophy [85], whether this is also associated with oxidative stress is less clear. In spontaneously hypertensive rats, the existence of an EGFR/NHE1 axis has been proposed as EGFR depletion led to reduction in NHE1 activity with accompanying attenuation of cardiac hypertrophy and decreased fractional shortening [86]. Although this signalling cascade requires further investigation, it can be speculated that NHE1 activation is ROS-dependent as EGFR depletion resulted in reduced NHE1 activity, albeit with no change in protein levels but with accompanying reductions in ROS and lipid peroxidation.…”

Section: Ion Channelsmentioning

confidence: 99%

Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets

Ramachandra

Cong

Chan

et al. 2021

Free Radical Biology and Medicine

View full text Add to dashboard Cite

“…diversos estudios de nuestro laboratorio demuestran que la sensibilidad es suficiente para detectar aumentos de •O2 − por encima del fondo, tanto en condiciones basales como luego de diversas intervenciones [136,137].…”

Section: Determinación De Anión Superóxido (•O2 − )unclassified

Modulación de la contractilidad cardíaca por p38-MAPK: rol del intercambiador Na+/H+ (NHE-1) y del estrés oxidativo

Zavala¹

View full text Add to dashboard Cite

El estiramiento miocárdico es un importante estímulo fisiológico que permite al corazón modular su función contráctil y, en consecuencia, adaptar el gasto cardíaco frente a los cambios en las condiciones hemodinámicas. Ha sido demostrado que el estiramiento del mismo induce un aumento de fuerza contráctil en dos fases: una fase rápida debida al mecanismo de Frank-Starling, seguida de una gradual llamada segunda fase de fuerza (SFF). Durante los últimos años, nuestro grupo de trabajo ha aportado sólidas evidencias científicas que demuestran que la SFF en respuesta a cambios de precarga es la expresión de un mecanismo autocrino/paracrino disparado por el estiramiento parietal, que desencadena una compleja ruta de señalización. Ésta vía inicia con la activación del receptor de AT1 de Angiotensina II (Ang II) y del ETA de Endotelina 1, aumento en la producción de especies reactivas del oxígeno (ROS) por parte de la mitocondria y activación de quinasas redox sensibles responsables de activar proteínas de membrana como el intercambiador Na+/H+ (NHE-1). L activación del NHE-1 resulta crucial para el desarrollo de la SFF, ya que su inhibición cancela dicha fase. Al estar activo produce un aumento en la concentración de Na+ intracelular, el cual promueve la activación del funcionamiento del modo reverso del intercambiador Na+/Ca2+ (NCXrev), con el consecuente incremento de Ca2+ intracelular, responsable final del aumento de fuerza de la SFF. Existe evidencia que demuestra que la p38-MAPK regula negativamente la actividad del NHE-1 inducida por Ang II, y que la actividad sostenida de esta quinasa disminuye la contractilidad cardíaca. A su vez, como se mencionó, nuestro grupo demostró que el incremento en la producción ROS inducidas por el estiramiento resulta crucial para el desarrollo de la SFF, debido a que promueven la activación de quinasas redox sensibles responsables de activar al NHE-1, y que, inhibir su producción, cancela el desarrollo de la SFF. En este contexto, el objetivo de este trabajo de Tesis Doctoral fue estudiar el rol de p38-MAPK, así como del estrés oxidativo, sobre la contractilidad miocárdica luego del estiramiento, poniendo especial atención en los posibles efectos sobre la actividad del NHE-1. El presente trabajo ha permitido aportar valiosas evidencias acerca del rol que ejerce la quinasa p38-MAPK sobre la SFF, y a su vez ha contribuido a un mayor entendimiento del papel que juegan las ROS sobre la misma.

show abstract

Silencing of epidermal growth factor receptor reduces Na+/H+ exchanger 1 activity and hypertensive cardiac hypertrophy

Cited by 5 publications

References 60 publications

Inhibition of the ROS-EGFR Pathway Mediates the Protective Action of Nox1/4 Inhibitor GKT137831 against Hypertensive Cardiac Hypertrophy via Suppressing Cardiac Inflammation and Activation of Akt and ERK1/2

Inhibition of the ROS-EGFR Pathway Mediates the Protective Action of Nox1/4 Inhibitor GKT137831 against Hypertensive Cardiac Hypertrophy via Suppressing Cardiac Inflammation and Activation of Akt and ERK1/2

Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets

Modulación de la contractilidad cardíaca por p38-MAPK: rol del intercambiador Na+/H+ (NHE-1) y del estrés oxidativo

Contact Info

Product

Resources

About