Cardiac injury modulates critical components of prostaglandin E(2) signaling during zebrafish heart regeneration

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.