摘要：The inability to effectively stimulate cardiomyocyte proliferation remains a principle barrier to regeneration in the adult human heart. A tightly regulated, acute inflammatory response mediated by a range of cell types is required to initiate regenerative processes. Prostaglandin E 2 (PGE 2 ), a potent lipid signaling molecule induced by inflammation, has been shown to promote regeneration and cell proliferation; however, the dynamics of PGE 2 signaling in the context of heart regeneration remain underexplored. Here, we employ the regeneration-competent zebrafish to characterize components of the PGE 2 signaling circuit following cardiac injury. In the regenerating adult heart, we documented an increase in PGE 2 levels, concurrent with upregulation of cox2a and ptges , two genes critical for PGE 2 synthesis. Furthermore, we identified the epicardium as the most prominent site for cox2a expression, thereby suggesting a role for this tissue as an inflammatory mediator. Injury also drove the opposing expression of PGE 2 receptors, upregulating pro-restorative ptger2a and downregulating the opposing receptor ptger3 . Importantly, treatment with pharmacological inhibitors of Cox2 activity suppressed both production of PGE 2 , and the proliferation of cardiomyocytes. These results suggest that injury-induced PGE 2 signaling is key to stimulating cardiomyocyte proliferation during regeneration.
