miR-378a-3p Promotes M2 Macrophage Polarization, Improving Cardiac Repair After Infarction Via Trem1

Early detection and effective treatment for Acute Myocardial Infarction (AMI) remain critical, as post-infarction cardiac remodeling often leads to heart failure. The inflammatory response following AMI, particularly macrophage polarization dynamics, profoundly influences cardiac repair outcomes. While M1 macrophages exacerbate inflammation, M2 macrophages promote healing. However, the precise regulatory roles of microRNAs in orchestrating this crucial macrophage shift for cardiac repair are largely undefined, representing a significant therapeutic gap.

Researchers conducted an integrated analysis of GEO datasets and performed experimental validation in hypoxic Raw264.7 cells and a mouse AMI model. In vitro, miR-378a-3p mimics were administered to cells. In vivo, miR-378a-3p agomir was delivered to mice with induced AMI. Primary endpoints included assessing macrophage polarization (M1 vs. M2), inflammatory cytokine production, and evaluating cardiac function and remodeling. The study also investigated the mechanistic interaction between miR-378a-3p and its target, Trem1, using overexpression experiments.

Integrated GEO datasets and experimental validation revealed that miR-378a-3p is significantly downregulated following ischemic injury. In both hypoxic Raw264.7 cells and the mouse AMI model, administration of miR-378a-3p mimics or miR-378a-3p agomir effectively suppressed M1 macrophage polarization. This intervention also attenuated inflammatory cytokine production, leading to markedly improved cardiac function and remodeling after AMI. Mechanistically, miR-378a-3p was found to directly bind the 3'UTR of Trem1 mRNA. > Overexpression of Trem1 reversed the anti-inflammatory and pro-repair effects of miR-378a-3p, definitively confirming Trem1 as a functional target in this pathway. This establishes the miR-378a-3p/Trem1 axis as a critical regulator of post-infarction inflammation.