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<p>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.</p>

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Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月5日

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  • Elin Svedlund Eriksson,
  • Marta Lantero Rodriguez,
  • Bente Halvorsen,
  • Inger Johansson,
  • Anna K. F. Mårtensson,
  • Anna S. Wilhelmson,
  • Camilla Huse,
  • Thor Ueland,
  • Pål Aukrust,
  • Kaspar Broch,
  • Lars Gullestad,
  • Brage Høyem Amundsen,
  • Geir Øystein Andersen,
  • Mikael C. I. Karlsson,
  • Malin Hagberg Thulin,
  • Alessandro Camponeschi,
  • Dana Trompet,
  • Ola Hammarsten,
  • Björn Redfors,
  • Jan Borén,
  • Elmir Omerovic,
  • Malin C. Levin,
  • Andrei S. Chagin,
  • Tuva B. Dahl,
  • Åsa Tivesten

摘要

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.