KLK8 modulates macrophage function following myocardial infarction by promoting the paracrine of epidermal growth factor from cardiac fibroblasts

Abstract

Aims

Tissue kallikrein-related peptidase 8 (KLK8) plays a significant role in the regulation of cardiac remodeling following myocardial infarction (MI). However, the impact of KLK8 on macrophage (MΦ) function in the context of MI remains to be elucidated.

Materials and methods

MI was induced through the ligation of the left anterior descending coronary artery for a duration of 1 h, followed by reperfusion. The morphological and molecular alterations in the heart were assessed at 24 h and 14 days post-ischemic injury. Adult rat cardiac fibroblasts and bone marrow-derived macrophages were employed to explore the underlying molecular mechanisms in vitro.

Key findings

In the acute phase of MI (24 h post-MI), KLK8 was observed to diminish the inflammatory response and mitigate tissue damage within the ischemic ventricle. Conversely, during the reparative phase of MI (14 days post-MI), KLK8 was found to enhance the accumulation of the M2 MΦs, elevate pro-fibrotic factors, and intensify cardiac fibrosis. The in vitro analysis revealed that KLK8 did not exert a direct effect on MΦs; rather, it facilitated the paracrine secretion of epidermal growth factor (EGF) from the cardiac fibroblasts. This EGF may play a role in inhibiting the pro-inflammatory activation of the MΦs and promoting their polarization towards the M2 phenotype under conditions of inflammatory stress.

Significance

In summary, KLK8 modulates MΦ function through the paracrine of EGF derived from cardiac fibroblasts, which may have implications for cardiac injury and remodeling following MI.