Targeting Siglec-E Modulates Macrophage Polarization to Attenuate Cardiac Remodeling After Myocardial Infarction.

Adverse cardiac remodeling after myocardial infarction (MI) is a major cause of heart failure. Macrophage polarization plays a pivotal role in this process. Siglec-E, an immunoregulatory molecule expressed on myeloid cells, modulates macrophage function, yet its specific role in post-MI cardiac remodeling remains unknown. Elucidating this role may reveal novel therapeutic strategies and provide critical safety insights for Siglec-E-targeted anticancer therapies. Siglec-9 (the human homolog of Siglec-E) expression was first identified in GEO datasets and validated by flow cytometry in a human cohort (AMI,controls,and CCS). Siglec-E expression was then examined in murine models of MI. To assess its functional role, Siglec-E⁻/⁻ and wild-type mice were subjected to permanent coronary artery ligation. Cardiac remodeling was evaluated by echocardiography and histopathological examination. Immune cell profiles, macrophage polarization, and inflammatory gene expression were analyzed by flow cytometry,immunofluorescence, and qPCR. Finally, macrophage depletion and adoptive transfer studies were performed to establish causality. Siglec-9/E expression was upregulated in monocytes/macrophages after MI in human and mice. Compared to WT controls, Siglec-E⁻/⁻ mice exhibited worsened survival, impaired cardiac function (reduced left ventricular ejection fraction and fractional shortening, increased ventricular volumes), larger infarct size, exacerbated fibrosis, and enhanced cardiomyocyte apoptosis after MI. Mechanistically, Siglec-E deficiency skewed cardiac macrophages toward a pro-inflammatory M1 phenotype, without affecting neutrophil recruitment. Macrophage depletion abolished the adverse phenotype in Siglec-E⁻/⁻ mice. Adoptive transfer of wild-type macrophages attenuated cardiac injury, whereas transfer of Siglec-E⁻/⁻ macrophages exacerbated adverse remodeling. Siglec-E is a key regulator of post-MI cardiac remodeling by restraining pro-inflammatory M1 macrophage polarization. Targeting macrophage Siglec-E signaling may represent a promising therapeutic strategy for heart failure.