Abstract P313: Knockout Or Antagonism Of The Prostaglandin E2 Ep3 Receptor Is Protective In A Mouse Model Of Myocardial Infarction

Abstract

Prostaglandin E 2 is an autacoid that acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that expression of the EP3 receptor increases after myocardial infarction (MI) and mediates reduced cardiac function. Moreover, we reported that a selective EP3 antagonist (L798,106) prevents reduced cardiac function in Angiotensin II hypertension. We therefore hypothesized that cardiomyocyte specific knock-out and/or pharmacological inhibition of EP3 protects the heart from cardiac dysfunction after MI. To test our hypothesis, we created a conditional cardiomyocyte-specific EP3 knockout mouse (EP3 KO) by crossing EP3 fl / fl mice with a tamoxifen-inducible αMHC-MerCreMer mouse. Fifteen-week-old male EP3 KO and EP3 fl / fl underwent sham or MI surgery. After 2 wks cardiac function was assessed by echo and western blot was performed. There were no significant differences in cardiac function between strains after sham operation. After MI, EP3 fl/fl mice showed significant reductions in ejection fraction (EF;68 ± 5.6 % sham vs 49.1 ± 5.2 % MI; p<0.05), coupled with increased left ventricle dimension at systole (LVDs;1.12 ± 0.08 mm sham vs 2.08 ± 0.34 mm MI; p< 0.05). However, these changes were not observed for EP3 KO mice post-MI. EF was 73.1 ± 0.68% in sham vs 69.0 ± 0.81% for MI; and LVDs was 1.09 ± 0.05 in sham vs 1.09 ± 0.04 for MI. Additionally, phosphorylated phospholamban protein levels were significantly reduced after MI in EP3 fl/fl mice (1.14 ± 0.2 A.U. in sham to 0.42 ± 0.2 A.U. in MI; p<0.05) whereas they were not altered after MI in EP3 KO mice (1.37 ± 0.5 A.U. in sham to 1.55 ± 0.4 A.U. in MI). We next determined whether daily treatment with L798, 106 would improve cardiac function post MI. C57BL/6 mice were subject to MI and assigned to vehicle or L798,106 treatment groups (40 μg/Kg/day, s.c.) 3 days post-surgery. After 2 wks, EF was improved from 36.4 ± 4.6 % in vehicle-treated mice to 47.3 ± 5.1% in mice receiving L798,106. Fractional shortening also was improved from 17.6 ± 2.5 % in vehicle-treated mice to 24.0 ± 2.9% in L798,106 -treated mice. Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function and future experiments are warranted to investigate the use of an EP3 antagonist as a potential therapeutic in heart failure.