Background: Following myocardial infarction (MI) the heart reactivates regenerative and growth pathways that were thought to be active only during embryonic development. One such pathway is the Wnt signaling pathway. Recently, macrophage-derived Wnt signaling has been proposed as a key mediator of inflammation and repair in different tissues. However, its exact role after MI remains unclear. Thus, we aimed to determine the role of macrophages in the activation of Wnt pathway responses in cardiac repair and regeneration.
Methods and Results: To assess Wnt signaling after MI, we subjected balbC mice to anterior MI or sham operation (controls). Hearts were harvested 4 days later for RNA purification and Wnt signaling analysis was performed using a real-time PCR array for Wnt pathway components. Notably, genes associated with active Wnt signaling, such as Wisp1, Lef1 and Fzd3 were up-regulated in the infarcted myocardium,
compared with controls. Furthermore, histology assessment of infarcted hearts showed this signaling to be highly expressed only in the infarct area, at the site of macrophage accumulation.
Next, we induced anterior MI in mice that could not produce Wnt ligands from macrophages (Cfms-icre;Wlsfl/fl).
We then evaluated cardiac function by echocardiography measurements, 1, 7 and 30 days after MI. Interestingly, we found that Wnt signaling ablation in macrophages had a protective effect against adverse cardiac remodeling and dysfunction. Specifically, LV dilatation was lower and ejection fraction was higher in mice with macrophage Wnt signaling deletion, compared with wild-types.
Conclusion: A Wnt signaling pathway is up-regulated in the infarcted heart. Our findings suggest that inhibition of this pathway in macrophages attenuates adverse LV remodeling and improves heart function. Thus, the macrophage-derived Wnt family of proteins could be a potential therapeutic target for cardiac repair and regeneration.
