Cardiac injury modulates critical components of prostaglandin E2 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 E₂ (PGE₂), a potent lipid signaling molecule induced by inflammation, has been shown to promote regeneration and cell proliferation; however, the dynamics of PGE₂ signaling in the context of heart regeneration remain underexplored. Here, we employ the regeneration-competent zebrafish to characterize components of the PGE₂ signaling circuit following cardiac injury. In the regenerating adult heart, we documented an increase in PGE₂ levels, concurrent with upregulation of cox2a and ptges, two genes critical for PGE₂ 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 PGE₂ receptors, upregulating pro-restorative ptger2a and downregulating the opposing receptor ptger3. Importantly, treatment with pharmacological inhibitors of Cox2 activity suppressed both production of PGE₂, and the proliferation of cardiomyocytes. These results suggest that injury-induced PGE₂ signaling is key to stimulating cardiomyocyte proliferation during regeneration.