Metoprolol disrupts inflammatory response of human cardiomyocytes via β-arrestin2 biased agonism and NF-κB signaling modulation.

Autor: Ricci F; Department of Neuroscience, Imaging and Clinical Sciences, G.d'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy and University Cardiology Division, Heart Department, SS Annunziata University Hospital, Chieti, Italy; Department of Clinical Sciences, Lund University, 214 28 Malmö, Sweden., Di Credico A; Department of Medicine and Aging Sciences, and Reprogramming and Cell Differentiation Lab, Center for Advanced Studies and Technology (CAST), G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy., Gaggi G; Department of Medicine and Aging Sciences, and Reprogramming and Cell Differentiation Lab, Center for Advanced Studies and Technology (CAST), G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy., Iannetti G; Department of Neuroscience, Imaging and Clinical Sciences, G.d'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy and University Cardiology Division, Heart Department, SS Annunziata University Hospital, Chieti, Italy., Ghinassi B; Department of Medicine and Aging Sciences, and Reprogramming and Cell Differentiation Lab, Center for Advanced Studies and Technology (CAST), G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy., Gallina S; Department of Neuroscience, Imaging and Clinical Sciences, G.d'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy and University Cardiology Division, Heart Department, SS Annunziata University Hospital, Chieti, Italy., Olshansky B; University of Iowa, Iowa City, IA, USA., Di Baldassarre A; Department of Medicine and Aging Sciences, and Reprogramming and Cell Differentiation Lab, Center for Advanced Studies and Technology (CAST), G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy. Electronic address: a.dibaldassarre@unich.it.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Oct 28; Vol. 168, pp. 115804. Date of Electronic Publication: 2023 Oct 28.
DOI: 10.1016/j.biopha.2023.115804
Abstrakt: Aims: Recent evidence supports non-class cardioprotective effects of metoprolol against neutrophil-mediated ischemia-reperfusion injury during exacerbated inflammation. Whether metoprolol exerts direct anti-inflammatory effect on cardiomyocytes is unknown. Accordingly, we aimed to investigate the direct anti-inflammatory effects of metoprolol in a cellular model of human induced pluripotent stem cell-derived cardiomyocytes (hiCMs) and to explore the role of β-arrestin2 (β-ARR2) biased agonism signaling pathway.
Methods and Results: hiCMs were treated with TNF-α for 24 h, followed by 4-hour treatment with metoprolol or esmolol. Electrical response of hiCMs to β1-selective blockade was assessed by microelectrode arrays technology. The effect on inflammatory and adhesion molecule expression was evaluated in wild-type and β-ARR2 silenced hiCMs. To silence β-ARR2 expression, hiCMs were transfected with a specific small interfering RNA targeting β-ARR2 mRNA and preventing its translation. TNF-α stimulation boosted the expression of IκB, NF-κB, IL1β, IL6, and VCAM1 in hiCMs. TNF-α-treated hiCMs showed similar physiological responses to metoprolol and esmolol, with no difference in field potential duration and beat period recorded. Adding metoprolol significantly decreased inflammatory response patterns in wild-type hiCMs by dampening TNF-α induced expression of NF-κB, IL1β, and IL6, but not in β-ARR2-knockout hiCMs. A similar response was not observed in presence of β1-selective blockade with esmolol.
Conclusions: Metoprolol exerts a non-class direct anti-inflammatory effect on hi-CMs. β1-selective blockade with metoprolol disrupts inflammatory responses induced by TNF-α and induces significant inhibition of NF-κB signaling cascade via β-ARR2 biased agonism. If confirmed at clinical level, metoprolol could be tested and repurposed to treat cardiac inflammatory disorders.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: