Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression

Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression

Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of h...

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Bibliographic Details
Main Authors: Asma S. Alonazi, Anfal F. Bin Dayel, Danah A. Albuaijan, Alhanouf S. Bin Osfur, Fatemah M. Hakami, Shaden S. Alzayed, Ahmad R. Almotairi, Mohammad R. Khan, Hana M. Alharbi, Rehab A. Ali, Maha A. Alamin, Hanan K. Alghibiwi, Nouf M. Alrasheed, Khaled A. Alhosaini
Format: Article
Language:English
Published: MDPI AG 2023-12-01
Series:International Journal of Molecular Sciences
Subjects:
GRK2
paroxetine
NF-κB
prohypertrophic genes
cardiac hypertrophy
Online Access:https://www.mdpi.com/1422-0067/24/24/17270
Description
Summary:Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (<i>p</i> < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (<i>p</i> < 0.001), BNP (<i>p</i> < 0.01), <i>ANP</i> (<i>p</i> < 0.001), hydroxyproline (<i>p</i> < 0.05), <i>TGF-β1</i> (<i>p</i> < 0.05), and <i>αSMA</i> (<i>p</i> < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (<i>p</i> < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.
ISSN:1661-6596
1422-0067

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