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

Abstract

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.

A Bioinformatics Investigation into the Pharmacological Mechanisms of Sodium-Glucose Co-transporter 2 Inhibitors in Diabetes Mellitus and Heart Failure Based on Network Pharmacology

“…Previous studies had indicated that inhibition of EGFR activity protected against progressive DN in T1 DM and T2 DM [ 48 ]. Zeng et al concluded that EGFR inhibition reduced ROS production in the left ventricle and blunted hypertensive myocardial hypertrophy in spontaneously hypertensive rats [ 49 ]. Therefore, the EGFR tyrosine kinase inhibitor resistance may have a common effect to accelerate the progression of DM with HF.…”

“…Edges represent proteinprotein associations, and the line thickness indicates the strength of data support. inhibition reduced ROS production in the left ventricle and blunted hypertensive myocardial hypertrophy in spontaneously hypertensive rats [49]. Therefore, the EGFR tyrosine kinase inhibitor resistance may have a common effect to accelerate the progression of DM with HF.…”

Cold Atmospheric Plasma Boosts Virus Multiplication via EGFR(Tyr1068) Phosphorylation-Mediated Control on Cell Mitophagy

“…Various evidences have supported the roles of EGFR in ROS-induced cellular response 32 - 37 . EGFR level was considerably reduced when cells were exposed to IBRV infection and 4-min CAP treatment followed by 46 h culturing (p<0.001, Figure 2 A ).…”

Setanaxib (GKT137831) Ameliorates Doxorubicin-Induced Cardiotoxicity by Inhibiting the NOX1/NOX4/Reactive Oxygen Species/MAPK Pathway

“…It is also well tolerated and delays or prevents the progression of a range of cardiovascular disorders. For example, GKT137831 attenuated plaque formation by inhibiting ROS generation and reducing the adhesion of inflammatory cells to the vascular wall ( Gray et al, 2013 ); it also markedly attenuated cardiac remodeling by decreasing ROS levels ( Zhao et al, 2015 ) and attenuated hypertensive cardiac hypertrophy by suppressing cardiac inflammation and activating Akt and ERK1/2 ( Zeng SY. et al, 2020 ).…”