Loss of macrophage fibroblast growth factor 12 attenuates cardiac fibrosis in pressure-overloaded myocardium.

BACKGROUND

Cardiac fibrosis, a leading cause of death worldwide, plays a functional role in the development of heart failure. Unfortunately, there are currently no therapeutic strategies in clinical practice that can specifically attenuate the activation of cardiac fibroblasts, the effector cells of fibrosis in the heart. In this study, we aimed to identify a novel approach to target myocardial fibrosis through the crosstalk between macrophages and fibroblasts.

METHODS

We investigated the expression of fibroblast growth factor 12 (FGF12), a novel regulator of macrophage activation, in both human subjects and mouse models. We also generated myeloid cell-specific FGF12 knockout mice to determine the role of FGF12 in cardiac fibrosis. For in vitro studies, we isolated mouse primary bone marrow-derived macrophages (BMDMs) and cardiac fibroblasts to explore the mechanism by which FGF12 controls macrophage polarization and fibroblast activation.

RESULTS

We found that FGF12 expression was significantly upregulated in both human failing hearts and mouse pressure-overloaded myocardium. RNA sequencing revealed that FGF12 upregulation was associated with fibrosis progression, oxidative stress response, and macrophage activation in mouse heart tissues. Myeloid-specific knockout of FGF12 markedly attenuated pressure overload-induced myocardial fibrosis in our mouse models. We observed that FGF12 significantly affects interleukin-4-stimulated M2 polarization in BMDMs. Conditioned medium from FGF12 knockdown or overexpressed BMDMs also influenced cardiac fibroblast activation, primarily by affecting reactive oxygen species (ROS) accumulation in cardiac fibroblasts. Furthermore, we demonstrated that FGF12 controls BMDM M2 polarization through the SOCS/STAT pathway.

CONCLUSIONS

FGF12 is a novel regulator of myocardial fibrosis, acting through the modulation of crosstalk between macrophages and fibroblasts. Therapeutic approaches targeting FGF12 may represent a potential strategy to ameliorate cardiac fibrosis or other fibrosis-related diseases in the future.