Ischemia/reperfusion injury (IRI) is a key process in the initiation of post-infarction pathological remodeling. Several studies demonstrated that platelets play a major role in the development of IRI due to their abundance at ischemic sites. Platelet activation leads to the secretion of platelet proteins, some of which (TGF-β, PDGF,..) are already involved in pathological ventricular remodeling. Among these, platelet factor 4 (PF4) is the most abundant chemokine and has already been implicated in the development of fibrosis in tissues such as the lung and skin.

To evaluate the role of platelet factor 4 (PF4) in cardiac fibroblasts differentiation and the subsequent development of cardiac fibrosis. Additionally, to determine whether targeting PF4 could serve as an innovative therapeutic strategy using human anti-PF4 monoclonal antibodies developed in our laboratory.

First, characterization of the effect of platelet factor 4 on cardiac fibroblasts primary culture by assessing fibrosis markers in normoxia condition or subjected to oxygen and nutrient deprivation stress. For therapeutic purposes, human anti-PF4 monoclonal antibodies previously developed in our laboratory (1E12, 1C12 and 5B9) were used to target the effect of PF4 in the differentiation of fibroblasts into myofibroblasts.

Our results show that PF4 (5μg/mL) induces a significant increase in α-sma (alpha-smooth muscle actin) expression in cardiac fibroblasts, under normoxic conditions as well as under conditions of nutrient and oxygen deprivation. Treatment of cardiac fibroblasts with a therapeutic concentration of heparin, which can interact with PF4 and is used as first-line therapy in post-infarction patients, had no effect on the PF4-induced increase in α-sma expression. However, anti-PF4 monoclonal antibodies significantly reduced the expression of the fibrosis marker expressed by FP4-induced cardiac fibroblasts.

This study demonstrates the role of PF4 in the differentiation of cardiac fibroblasts towards the myofibroblastic profile, which initiates fibrosis. Furthermore, the use of anti-PF4 antibodies decreases PF4-dependent cardiac fibroblast differentiation in normoxia and under conditions of nutrient and oxygen stress, suggesting a potential innovative strategy for targeting fibrosis associated with pathological left ventricular remodeling after myocardial infarction.