Abstract P2014: Knockout Of Prostaglandin E2 Ep3 Receptor Improves Cardiac Function In Both Sexes 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. This effect was exacerbated in mice that overexpress EP3 in the cardiomyocytes. Furthermore, we reported that the EP3 receptor antagonist, L798106 reduced blood pressure in the Angiotensin II hypertension model and improved cardiac function. We therefore hypothesized that cardiomyocyte specific knock-out of EP3 (EP3 KO) and/or pharmacological antagonism of EP3 protects the heart from cardiac dysfunction after MI. To test our hypothesis, we created a cardiomyocyte specific (αMHC promoter), tamoxifen inducible CM-EP3 KO mouse. Fifteen-week-old male and female EP3 KO and floxed controls underwent sham or MI surgery. After 2 wks, echocardiography was performed, and all statistical analysis was performed by a biostatistician at Henry Ford Health. There were no significant differences in cardiac function between strains after sham operation. After 2 wks MI, male floxed control 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). Remarkably, 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. Similarly, EF was 66.3 ± 2.4% in female sham mice and remained unchanged after MI (EF; 62.7 ± 2.3% in EP3 KO MI). To investigate a more translational and therapeutic approach, we examined whether daily administration of L798106 improves cardiac function post MI. Male C57BL/6 mice were subject to MI and assigned to vehicle or L798106 treatment (40 μg/Kg/day, s.c.) beginning 3 days post-surgery. After 2 wks, EF was substantially improved from 36.0 ± 2.6% in vehicle vs 49.4 ± 3.0% in L798106, p<0.01. Similar improvements were observed in fractional shortening. 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.