2. Academic Validation
  3. Endothelial NADPH oxidase 5 overexpression promotes thrombosis and alters thrombus composition by sex-dependent mechanisms in mice

Endothelial NADPH oxidase 5 overexpression promotes thrombosis and alters thrombus composition by sex-dependent mechanisms in mice

  • J Thromb Haemost. 2025 Sep;23(9):2858-2872. doi: 10.1016/j.jtha.2025.05.015.
Javier Marqués 1,  Joaquín Fernández-Irigoyen 2,  María Martínez-Azcona 1,  Elena Ainzúa 1,  Victor Marqués 1,  Carmen Roncal 3,  Josune Orbe 4,  Enrique Santamaría 2,  Guillermo Zalba 5
Affiliations

Affiliations

  • 1 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Biochemistry and Genetics Department, University of Navarra, Pamplona, Spain.
  • 2 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain.
  • 3 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima, University of Navarra, Pamplona, Spain; CIBERCV, ISCIII, Madrid, Spain.
  • 4 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima, University of Navarra, Pamplona, Spain; RICORS-Cerebrovascular Diseases, Instituto de Salud Carlos III, Madrid, Spain.
  • 5 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Biochemistry and Genetics Department, University of Navarra, Pamplona, Spain. Electronic address: gzalba@unav.es.
PMID: 40436274 DOI: 10.1016/j.jtha.2025.05.015
Abstract

Background: Different members of the NADPH oxidases family (NOXs) participate in thrombosis. Nevertheless, the information about NOX5 in this process is scarce.

Objectives: The aim of this study was to test whether chronic expression of NOX5 may modulate thrombosis.

Methods: To test this hypothesis, mice expressing human NOX5 at the endothelium and their control littermates underwent a FeCl3-induced thrombosis model in the carotid artery. The composition of the thrombi obtained from these mice was analyzed by proteomics. The derived findings were corroborated by molecular analysis in vivo, in vitro, and ex vivo. Finally, the antithrombic effects of N-acetylcysteine and the pan-NOX inhibitor ML090 were tested.

Results: The results from this assay indicate that endothelial NOX5 expression promotes thrombosis in vivo in a sex-dependent manner. In female mice, NOX5 enhances prostaglandin E2 secretion and alters the expression of endothelial adhesion molecules. In male mice, NOX5 partially promotes the activation of circulating neutrophils. Both, N-acetylcysteine and ML090 protect against thrombosis in vivo.

Conclusion: In conclusion, our findings demonstrate that endothelial NOX5 plays a role in thrombosis, indicating that this oxidase should be considered as a therapeutic target to prevent thrombosis.

Keywords

NADPH oxidase 5; NADPH oxidases; endothelial cells; proteomics; thrombosis.

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