Abstract 727: Cardiac Overexpression of the EP3 Receptor Induces Left Ventricular Eccentric Hypertrophy
The expression of cyclooxygenase (COX-2) is strongly enhanced in acute myocardial ischemia/reperfusion, accompanied by an increased generation of prostaglandin E2 (PGE2). The inhibition of prostaglandin formation reduces hypertrophy and fibrosis in a mouse model of myocardial infarction. This suggests a contribution of PGE2 to cardiac remodeling and functional impairment after myocardial ischemia. Moreover, PGE2 has been shown to stimulate cardiomyocyte growth in vitro. The involvement of E-type prostaglandin receptors, namely the EP1, EP3 and EP4 subtype has been hypothesized. To study the potential role of the Gi/Gq coupled EP3 receptor in PGE2-induced hypertrophy, we generated transgenic (tg) mice with cardiospecific overexpression (49-fold) of the EP3 receptor. Magnetic resonance imaging indicated a significant increase in enddiastolic and endsystolic volume in tg hearts as compared to wild-type (wt) littermates (EDV: 125 ± 5 μl vs. 52 ± 3, ESV: 75 ± 6 vs. 10 ± 1 μl). LV ejection fraction was severely decreased in these hearts compared to wt (40 ± 4 vs. 82 ± 1 %, p < 0.01), while relative LV mass was significantly increased in tg animals (5.0 ± 0.2 vs. 2.7 ± 0.1 mg/g). Crossbreeding of EP3 tg animals with mice expressing a Gq inhibitory peptide led to offspring with reduced Gq signaling still exhibiting cardiac hypertrophy, suggesting dependence on Gi signaling. Analysis of signaling pathways involved in the hypertrophic response showed increased calcineurin activity and nuclear content of GATA4 in tg hearts, as compared to wt hearts. Microarray analysis revealed enhanced expression of atrial natriuretic factor and matrix compounds (decorin, collagen, biglycan), which was accompanied by cardiac fibrosis. Moreover, expression levels of thrombospondin-1, transforming growth factor-beta and connective tissue growth factor were elevated. We conclude that inhibitory G protein (Gi)-dependent EP3 receptor signaling results in a remarkable left ventricular eccentric hypertrophy, indicating an involvement of the EP3 receptor subtype in PGE2-mediated cardiomyocyte growth.