Prostaglandin E2 affects mitochondrial function in adult mouse cardiomyocytes and hearts.

• IPA of EP4 KO reveals changes in OXPhos and Mito dysfunction pathways. • Electron microscopy of EP4 KO cardiomyocytes reveal disordered cristae. • Cardiomyocytes from EP4 KO have reduced ATP levels. • PGE2 treatment reduces complex 1 activity in isolated cardiac myocytes. • Mito ROS is increased in EP4 KO cardiac myocytes or in myocytes treated with PGE2. Prostaglandin E2 (PGE2) signals differently through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic/pathologic effects. We previously reported that PGE2 via its EP3 receptor reduces cardiac contractility and male mice with cardiomyocyte-specific deletion of the EP4 receptor (EP4 KO) develop dilated cardiomyopathy. The aim of this study was to identify pathways responsible for this phenotype. We performed ingenuity pathway analysis (IPA) and found that genes differentiating WT mice and EP4 KO mice were significantly overrepresented in mitochondrial (adj. p value = 6.28 × 10⁻²⁶) and oxidative phosphorylation (adj. p value = 1.58 × 10⁻²⁷) pathways. Electron microscopy from the EP4 KO hearts show substantial mitochondrial disarray and disordered cristae. Not surprisingly, isolated adult mouse cardiomyocytes (AVM) from these mice have reduced ATP levels compared to their WT littermates and reduced expression of key genes involved in the electron transport chain (ETC) in older mice. Moreover, treatment of AVM from C57Bl/6 mice with PGE2 or the EP3 agonist sulprostone resulted in changes of various genes involved in the ETC, measured by the Mitochondrial Energy Metabolism RT²-profiler assay. Lastly, the EP4 KO mice have reduced expression of superoxide dismuatse-2 (SOD2), whereas treatment of AVM with PGE2 or sulprostone increase superoxide production, suggesting increased oxidative stress levels in these EP4 KO mice. Altogether the current study supports the premise that PGE2 acting via its EP4 receptor is protective, while signaling through its other receptors, likely EP3, is deleterious. [ABSTRACT FROM AUTHOR]