Abstract 33: Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor
Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 are present in the heart and signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop a phenotype of dilated cardiomyopathy with reduced ejection fraction. We thus hypothesized that PGE2 decreases contractility via EP3. To test this hypothesis, the effects of PGE2 and the EP1/EP3 agonist sulprostone (sulp) were examined in the mouse langendorff preparation and in adult mouse cardiomyocytes (AVM) using the IonOptix cell contractility system. Isolated hearts of 18-20 wk old male C57Bl/6 mice were mounted and equilibrated for 10 min, then perfused with PGE2 (10-6mol/l) or sulp (10-6mol/l) for 30 min. Values at the end of equilibration were set to 100%. Compared to vehicle, PGE2 decreased +dp/dt (77.8±3% vs 96.7±3%, p<0.01) and left ventricular developed pressure, LVDP (77.2±2% vs 96.8±3%, p<0.001). Sulp decreased +dp/dt (75.9±2% vs 96.7±3%, p<0.001), -dp/dt (72.2±1% vs 85.7±1%, p<0.01) and LVDP (70.9±1% vs 96.8±3%, p<0.001). The effects of both PGE2 and sulp were reversed by the EP3 antagonist, L789,106 (10-6mol/l). Myocyte contractility was evaluated on the IonOptix system with pacing at 1Hz. Treatment with PGE2 (10-9M) for 10 min reduced contractility as measured by peak height (3.69 ± 0.48% for vehicle vs 2.00 ± 0.22% for PGE2, p < 0.05 ), departure velocity (-171.9 ± 22.9 um/sec for vehicle vs -106.3± 12.5 um/sec for PGE2, p < 0.05) and return velocity (87.7 ± 16.3 um/sec for vehicle vs 36.7 ± 6.6 um/sec for PGE2, p < 0.05) with similar effects noted for sulp. Sulp reduced change in peak height (4.79 ± 1.15% for vehicle vs 1.81 ± 0.37% for sulp, p < 0.05), departure velocity (-169.1 ± 35.8 um/sec for vehicle vs -59.4 ± 10.3 um/sec for sulp, p < 0.05) and return velocity (86.5 ± 23.8 um/sec for vehicle vs 16.9 ± 14.7 um/sec for sulp, p < 0.05). We then examined the acute effects of PGE2 and sulp on expression of phosphorylated phospholamban (PLN) and SERCA using Western blot. Treatment of AVM for 15min with either PGE2 or sulp decreased expression of phosphorylated PLN corrected to total PLN, by 67% and 43%. SERCA2a expression was unaffected. In conclusion, PGE2 and sulp reduce contractility via the EP3 receptor through effects on PLN.
Author Disclosures: X. Gu: None. J. Xu: None. X. Yang: None. E. Peterson: None. P. Harding: 2. Research Grant; Significant; NIH Funding P01 HL28982-31A1.
- © 2015 by American Heart Association, Inc.