2. Academic Validation
  3. Piezo1 Upregulation in Monocyte-Derived Macrophages Impairs Post-Myocardial Infarction Cardiac Repair via Defective Efferocytosis and Enhanced Ferroptosis

Piezo1 Upregulation in Monocyte-Derived Macrophages Impairs Post-Myocardial Infarction Cardiac Repair via Defective Efferocytosis and Enhanced Ferroptosis

  • Adv Sci (Weinh). 2025 Nov 10:e10991. doi: 10.1002/advs.202510991.
Lu Peng 1,  Yunlong Xia 1,  Huishou Zhao 1,  Yongzhen Guo 1 2,  Xiaoming Xu 1,  Xue Han 1,  Shiyue Wang 1,  Fengyue Ding 1,  Quanchi Liu 1,  Congye Li 1,  Yuan He 1,  Zhaoyi Luo 1,  Qiaojuan Wang 1,  Xing Zhang 3,  Feng Gao 3,  Yajing Wang 4,  Yulin Li 5,  Shengpeng Wang 6,  Ling Tao 1,  Wenjun Yan 1 7
Affiliations

Affiliations

  • 1 Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
  • 2 School of Public Management, Northwest University, Xi'an, 710127, China.
  • 3 Key Laboratory of Aerospace Medicine of the Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.
  • 4 Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35294, United States of America.
  • 5 Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
  • 6 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710069, China.
  • 7 Department of Toxicology, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
PMID: 41214880 DOI: 10.1002/advs.202510991
Abstract

The regulation of macrophage function, particularly that of monocyte-derived macrophages (MoMs), by mechanical forces during myocardial infarction (MI) remains poorly understood. Consistently upregulated Piezo1 expression in cardiac macrophages and MoMs post-MI is found. Elevated Piezo1 expression in MoMs directly contributes to increased Piezo1 levels in cardiac macrophages. Myeloid cell-specific Piezo1-deficient mice (Piezo1Lyz2) exhibit significant improvements in ventricular function/remodeling after MI, accompanied by decreased apoptotic cardiomyocytes and decreased inflammation, increased numbers of macrophages, and increased border zone efferocytosis. In vitro, Piezo1 activation by Yoda1 increased oxygen-glucose deprivation (OGD)-induced Ferroptosis and impaired MoM efferocytosis. Conversely, Piezo1 deficiency in MoMs decreases Ferroptosis and increases efferocytosis. SLC7A11 is shown to mediate Piezo1-induced defective efferocytosis in MoMs. Piezo1 activation aggravated OGD-induced macrophage Ferroptosis via CA2+ influx followed by SLC15A3 upregulation. Piezo1 upregulated SLC7A11 in macrophages via a CA2+/ATF4-dependent pathway. MoM-specific SLC7A11 knockdown significantly increases efferocytosis, reduces cardiomyocyte Apoptosis and inflammation, and ameliorates post-MI left ventricular remodeling and function. In conclusion, early Piezo1 activation in MoMs is identified during MI, which governs the fate and function of recruited macrophages. These data establish an ischemic heart-bone marrow functional network and provide a novel therapeutic strategy in which MoM Piezo1 is targeted for post-MI heart repair.

Keywords

Piezo1; SLC15A3; SLC7A11; macrophages; myocardial infarction.

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