Loss of Macrophage-Wnt Signaling Improves Remodeling and Function after MI in Mice

Background: Although the role of Wnt ligands in cardiac development, activation of cardiac progenitors, and cardiac response to injury is well established, their role in the macrophage-regulated inflammatory response after myocardial infarction (MI) remains unknown. Therefore, we aimed to determine the role of macrophage Wnt pathway signaling in cardiac repair and regeneration using a conditional cre-lox transgenic strategy.

Methods and Results: To assess Wnt signaling after MI, we induced anterior MI in Axin2-Lacz reporter mice, which revealed robust Wnt signaling at the infarct zone, compared with sham-operated reporter mice. To determine whether infarct macrophages are a source of Wnt ligands after MI, we assessed levels of mRNAs encoding Wnt pathway genes in isolated infarct macrophages. This analysis demonstrated that infarct macrophages express distinct Wnt pathway components in response to MI, including non-canonical Wnt ligands. To determine the effect of macrophage-derived Wnt ligands on cardiac repair, we induced anterior MI in transgenic mice whose macrophages were unable to secrete Wnt ligands (Cfms-icre; Wls ^fl/fl). Significantly, deletion of macrophage Wnt signaling induced a unique reparative, pro-angiogenic phenotype in infarct macrophages, assessed by cytokine secretion, gene expression and flow cytometry assays. We then evaluated cardiac function by speckle-tracking echocardiography at baseline and at 1, 7 and 30 days after MI. We found that Wnt signaling ablation in macrophages prevented adverse cardiac remodeling and improved infarct vascularization, infarct-related segmental wall motion, as well as global cardiac function after MI.

Conclusion: Inhibition of Wnt signaling in macrophages improves heart function, attenuates adverse cardiac remodeling and increases neovascularization after MI. Our findings suggest a new therapeutic target to improve infarct repair and regeneration.