Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow
Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI.
Authors
- Ola Hammarsten (ORCID: https://orcid.org/0000-0002-0772-6934)
- Geir Øystein Andersen (ORCID: https://orcid.org/0000-0003-1578-6440)
- Pål Aukrust
- Lars Gullestad (ORCID: https://orcid.org/0000-0002-5932-6641)
- Andrei S. Chagin (ORCID: https://orcid.org/0000-0002-2696-5850)
- Björn Redfors (ORCID: https://orcid.org/0000-0002-4155-4451)
- Kaspar Broch (ORCID: https://orcid.org/0000-0003-4316-805X)
- Bente Lise Halvorsen (ORCID: https://orcid.org/0000-0002-6529-6485)
- Åsa Tivesten (ORCID: https://orcid.org/0000-0002-8318-0486)
- Thor Ueland (ORCID: https://orcid.org/0000-0001-5005-0784)
- Marta Lantero Rodriguez (ORCID: https://orcid.org/0000-0002-9912-6716)
- Anna S. Wilhelmson (ORCID: https://orcid.org/0000-0003-0640-0251)
- Dana Trompet (ORCID: https://orcid.org/0000-0001-9472-6184)
- Jan Borén (ORCID: https://orcid.org/0000-0003-0786-8091)
- Alessandro Camponeschi (ORCID: https://orcid.org/0000-0002-6472-2438)
- Malin Hagberg Thulin (ORCID: https://orcid.org/0000-0002-8673-1247)
- Malin Levin (ORCID: https://orcid.org/0000-0003-1069-5275)
- Brage H. Amundsen (ORCID: https://orcid.org/0000-0001-7914-7395)
- Camilla Huse (ORCID: https://orcid.org/0000-0002-7694-5196)
- Mikael C. I. Karlsson (ORCID: https://orcid.org/0000-0001-5582-614X)
- Elmir Ömerovic (ORCID: https://orcid.org/0000-0002-3875-8621)
- Anna K. F. Mårtensson
- Tuva Børresdatter Dahl (ORCID: https://orcid.org/0000-0001-7818-9411)
- Elin Svedlund Eriksson
- Inger Johansson (ORCID: https://orcid.org/0009-0008-3579-9031)
Institutions
- University of Copenhagen (DK)
- Oslo University Hospital (NO)
- Brigham and Women's Hospital (US)
- University Hospital of North Norway (NO)
- Karolinska University Hospital (SE)
- Harvard University (US)
- University of Oslo (NO)
- Norwegian University of Science and Technology (NO)
- Sahlgrenska University Hospital (SE)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- Karolinska Institutet (SE)
- Region Västra Götaland (SE)
- St Olav's University Hospital (NO)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1038/s41467-025-56217-x
- Citations
- 14
- Primary Topic
- Adipokines, Inflammation, and Metabolic Diseases
- Type
- article
- Field-Weighted Citation Impact
- 18.96
Funders
- Hjärt-Lungfonden
- Vetenskapsrådet
- Göteborgs Universitet
- Science for Life Laboratory
- Novo Nordisk Fonden
- Sahlgrenska Akademin