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Therapeutic S100A8/A9 inhibition reduces NADPH oxidase expression, reactive oxygen species production and NLRP3 inflammasome priming in the ischemic myocardium

Vlad, Mihaela Loredana ; Mares, Razvan Gheorghita LU ; Jakobsson, Gabriel LU ; Manea, Simona Adriana ; Lazar, Alexandra Gela ; Preda, Mihai Bogdan ; Popa, Mirel Adrian ; Simionescu, Maya ; Schiopu, Alexandru LU orcid and Manea, Adrian (2025) In European Journal of Pharmacology 996.
Abstract

Oxidative stress and alterations in redox signalling have been implicated in the pathophysiology of myocardial infarction (MI). NADPH oxidase (Nox) is an important source of reactive oxygen species (ROS) in the infarcted myocardium. Alarmin S100A8/A9 amplifies acute myocardial inflammation in MI and has been shown to be a promising therapeutic target to improve cardiac function post-MI. We aimed to elucidate the underlying mechanisms linking S100A8/A9, oxidative stress and the inflammatory response in MI. MI was induced by permanent left coronary artery ligation in C57BL/6J mice, followed by treatment with the S100A8/A9 inhibitor ABR-238901 (30 mg/kg) or PBS for 3 days. The in-vivo experiments were complemented with mechanistic studies... (More)

Oxidative stress and alterations in redox signalling have been implicated in the pathophysiology of myocardial infarction (MI). NADPH oxidase (Nox) is an important source of reactive oxygen species (ROS) in the infarcted myocardium. Alarmin S100A8/A9 amplifies acute myocardial inflammation in MI and has been shown to be a promising therapeutic target to improve cardiac function post-MI. We aimed to elucidate the underlying mechanisms linking S100A8/A9, oxidative stress and the inflammatory response in MI. MI was induced by permanent left coronary artery ligation in C57BL/6J mice, followed by treatment with the S100A8/A9 inhibitor ABR-238901 (30 mg/kg) or PBS for 3 days. The in-vivo experiments were complemented with mechanistic studies on cultured macrophages (Mac), important cellular effectors in MI. Compared to sham-operated animals, we detected significant increases in the Nox1, Nox2, Nox4 catalytic subunits at mRNA and protein levels, and NADPH-dependent ROS production in the left ventricle of MI mice. S100A8/A9 blockade prevented the up-regulation of Nox1/2/4 expression, reduced ROS formation, suppressed NF-kB activation and prevented NLRP3 inflammasome priming and activation, leading to reduced levels of active IL-1β. In-vitro, S100A8/A9 induced gene expression of Nox catalytic subtypes and NLRP3 in Mac in a TLR4-dependent and dose-dependent manner. These effects were counteracted by pharmacological inhibition of S100A8/9, TLR4, Nox1/4 and Nox2. In conclusion, we show that Nox upregulation and ROS formation triggered by S100A8/A9 contributes to NLRP3 inflammasome priming and increased IL-1β production in the infarcted myocardium. These mechanisms can be therapeutically targeted to prevent inflammatory and oxidant myocardial damage in acute MI.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Myocardial infarction, NADPH oxidase, NLRP3 inflammasome, S100A8/A9
in
European Journal of Pharmacology
volume
996
article number
177575
publisher
Elsevier
external identifiers
  • pmid:40180274
  • scopus:105001724196
ISSN
0014-2999
DOI
10.1016/j.ejphar.2025.177575
language
English
LU publication?
yes
id
bd1f652b-39e0-4fde-8efd-6b4692e9012e
date added to LUP
2025-08-07 13:06:53
date last changed
2025-08-21 14:22:37
@article{bd1f652b-39e0-4fde-8efd-6b4692e9012e,
  abstract     = {{<p>Oxidative stress and alterations in redox signalling have been implicated in the pathophysiology of myocardial infarction (MI). NADPH oxidase (Nox) is an important source of reactive oxygen species (ROS) in the infarcted myocardium. Alarmin S100A8/A9 amplifies acute myocardial inflammation in MI and has been shown to be a promising therapeutic target to improve cardiac function post-MI. We aimed to elucidate the underlying mechanisms linking S100A8/A9, oxidative stress and the inflammatory response in MI. MI was induced by permanent left coronary artery ligation in C57BL/6J mice, followed by treatment with the S100A8/A9 inhibitor ABR-238901 (30 mg/kg) or PBS for 3 days. The in-vivo experiments were complemented with mechanistic studies on cultured macrophages (Mac), important cellular effectors in MI. Compared to sham-operated animals, we detected significant increases in the Nox1, Nox2, Nox4 catalytic subunits at mRNA and protein levels, and NADPH-dependent ROS production in the left ventricle of MI mice. S100A8/A9 blockade prevented the up-regulation of Nox1/2/4 expression, reduced ROS formation, suppressed NF-kB activation and prevented NLRP3 inflammasome priming and activation, leading to reduced levels of active IL-1β. In-vitro, S100A8/A9 induced gene expression of Nox catalytic subtypes and NLRP3 in Mac in a TLR4-dependent and dose-dependent manner. These effects were counteracted by pharmacological inhibition of S100A8/9, TLR4, Nox1/4 and Nox2. In conclusion, we show that Nox upregulation and ROS formation triggered by S100A8/A9 contributes to NLRP3 inflammasome priming and increased IL-1β production in the infarcted myocardium. These mechanisms can be therapeutically targeted to prevent inflammatory and oxidant myocardial damage in acute MI.</p>}},
  author       = {{Vlad, Mihaela Loredana and Mares, Razvan Gheorghita and Jakobsson, Gabriel and Manea, Simona Adriana and Lazar, Alexandra Gela and Preda, Mihai Bogdan and Popa, Mirel Adrian and Simionescu, Maya and Schiopu, Alexandru and Manea, Adrian}},
  issn         = {{0014-2999}},
  keywords     = {{Myocardial infarction; NADPH oxidase; NLRP3 inflammasome; S100A8/A9}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{European Journal of Pharmacology}},
  title        = {{Therapeutic S100A8/A9 inhibition reduces NADPH oxidase expression, reactive oxygen species production and NLRP3 inflammasome priming in the ischemic myocardium}},
  url          = {{http://dx.doi.org/10.1016/j.ejphar.2025.177575}},
  doi          = {{10.1016/j.ejphar.2025.177575}},
  volume       = {{996}},
  year         = {{2025}},
}