Abstract 488: Overexpression of the Prostaglandin E2 EP3 Receptor Reduces Cardiac Function in an Angiotensin II Model of Hypertension

Abstract

Prostaglandin E2 (PGE2) EP receptor subtypes 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, that PGE2 decreases contractility via EP3 in vivo, in vitro and ex vivo; and that EP3 expression in the heart increases when mice are subjected to Angiotensin (Ang) II-hypertension (HTN). We therefore hypothesized that overexpression of EP3 in the heart would exacerbate Ang II-HTN. To test this hypothesis, we used 10-12 week old male EP3 transgenic (Tg) mice with EP3 overexpression in cardiomyocytes and their wild type (WT) controls infused with either vehicle or 1.4 mg/kg/d Ang II for 2 weeks. Echocardiography was performed on conscious mice at the end of the experiment and systolic blood pressure (SBP) was measured every 2 days by tail cuff. Results: Table 1. All data are reported as means ± SEM. N= 3-6 mice per group. Statistical significance: * and *** p < 0.05 and p < 0.005 vs WT + vehicle, ++ p < 0.01 vs WT + Ang II, §§§ p < 0.005 vs Tg + vehicle. As shown in the table, cardiac function was unaffected in WT mice after Ang II infusion. Baseline cardiac function was reduced in EP3 Tg mice receiving vehicle and in contrast to WT mice, was further diminished after Ang II infusion. These differences were not due to altered systolic blood pressure. In conclusion, EP3 Tg mice present with reduced cardiac function at baseline and in support of our hypothesis, exhibit an enhanced response to Ang II. Antagonism of the EP3 receptor may be a novel treatment for heart failure associated with hypertension.