Metoprolol disrupts inflammatory response of human cardiomyocytes via β-arrestin2 biased agonism and NF-κB signaling modulation
(2023) In Biomedicine and Pharmacotherapy 168.- Abstract
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... (More)
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.
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- author
- Ricci, Fabrizio LU ; Di Credico, Andrea ; Gaggi, Giulia ; Iannetti, Giovanni ; Ghinassi, Barbara ; Gallina, Sabina ; Olshansky, Brian and Di Baldassarre, Angela
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Biased agonism, Cardiomyocyte, Inflammation, Metoprolol, β-arrestin
- in
- Biomedicine and Pharmacotherapy
- volume
- 168
- article number
- 115804
- publisher
- Elsevier
- external identifiers
-
- scopus:85175044330
- ISSN
- 0753-3322
- DOI
- 10.1016/j.biopha.2023.115804
- language
- English
- LU publication?
- yes
- id
- b268f978-de1a-4340-ac06-a931cd30dd91
- date added to LUP
- 2023-12-07 15:08:46
- date last changed
- 2023-12-07 15:09:43
@article{b268f978-de1a-4340-ac06-a931cd30dd91,
abstract = {{<p>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.</p>}},
author = {{Ricci, Fabrizio and Di Credico, Andrea and Gaggi, Giulia and Iannetti, Giovanni and Ghinassi, Barbara and Gallina, Sabina and Olshansky, Brian and Di Baldassarre, Angela}},
issn = {{0753-3322}},
keywords = {{Biased agonism; Cardiomyocyte; Inflammation; Metoprolol; β-arrestin}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Biomedicine and Pharmacotherapy}},
title = {{Metoprolol disrupts inflammatory response of human cardiomyocytes via β-arrestin2 biased agonism and NF-κB signaling modulation}},
url = {{http://dx.doi.org/10.1016/j.biopha.2023.115804}},
doi = {{10.1016/j.biopha.2023.115804}},
volume = {{168}},
year = {{2023}},
}