Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Abstract

Background Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop dilated cardiomyopathy with reduced ejection fraction. We thus hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3. Methods and Results The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse langendorff preparation and in adult mouse cardiomyocytes (AVM). Isolated hearts of adult male C57Bl/6 mice were perfused with PGE2 (10−6M) or sulp (10−6M) and compared to vehicle. Both PGE2 and sulprostone decreased +dp/dt (p<0.01) and left ventricular developed pressure, LVDP, (p<0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. AVM contractility was also reduced after treatment with either PGE2 or sulprostone for 10 min. We then examined the acute effects of PGE2, sulprostone and the EP4 agonist on expression of phosphorylated phospholamban (PLN) and SERCA2a in AVM using Western blot. Treatment with either PGE2 or sulprostone decreased expression of phosphorylated PLN corrected to total PLN whereas treatment with the EP4 agonist had the opposite effect. SERCA2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure volume loops. Both PGE2 and sulprostone decreased +dp/dt while the EP4 agonist increased +dp/dt. Conclusions Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in PLN phosphorylation and has relevance to detrimental effects of inflammation.

Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction

“…Since we also recently reported that PGE 2 via its EP3 receptor reduced contractility of the heart via mechanism(s) that appeared to involve decreased phospholamban phosphorylation; we examined phosphorylation of phospholamban in these studies. Sham-operated mice who received AAV9-EP4 exhibited a significant increase in phosphorylated phospholamban, consistent with our in vitro data using the EP4 agonist in isolated cardiomyocytes [4]. A similar trend was observed in animals with MI, although the data did not achieve statistical significance.…”

“…These effects appeared to involve changes in the phosphorylation of phospholamban. Moreover, we also reported that after MI, expression of the EP3 receptor subtype in the left ventricle was increased to a greater extent than EP4 [4]. We therefore hypothesized that overexpression of EP4 in the heart would improve cardiac function after MI.…”

“…Phospholamban (PLN), phosphorylated PLN (p-PLN), and HA-EP4 expression were measured by Western Blot using homogenized left ventricles from sham and MI mice who received either AAV9-EP4 or AAV9-Luc, as we have previously described [4]. The p-PLN antibody is from Cell Signaling (Danvers, MA) and recognizes phosphorylation at Ser16/Thr17.…”

“…Our laboratory has studied the role of PGE 2 via its EP4 receptor over the last decade and reported that the EP4 receptor causes hypertrophy of cardiac myocytes in vitro; that deletion of the EP4 receptor only in the cardiac myocyte worsens cardiac function after myocardial infarction (MI) and that male mice with cardiomyocyte deletion of the EP4 receptor develop a dilated cardiomyopathy with age that is characterized by reduced ejection fraction, left ventricle dilation, thinning of the posterior wall, and an increased interstitial cellular infiltrate [1–3]. Moreover, we recently reported that PGE 2 via its EP3 receptor could reduce contractility of preparations ranging from isolated myocytes to the whole heart by mechanisms that appeared to involve decreased phosphorylation of phospholamban (PLN) [4]. Presumably, this would lead to an inhibitory effect on SERCA, thereby decreasing contraction.…”

Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts

“…Oxylipins have many biological functions, and several effects of free oxylipins on the heart in health and disease have been shown (3,4) . For example, ARA-derived PGE 2 modulates cardiac contractility depending on which receptor it activates (5) , 19-hydroxyeicosatetraenoic acid (19-HETE) reduces cardiomyocyte hypertrophy (6) , 20-HETE and epoxy-eicosatrienoic acids (EpETrE) induce cardiac hypertrophy (7) , EpETrE prevent lipopolysaccharide-induced cardiac dysfunction (8) and 5-, 12and 15-HETE induce cellular hypertrophy in human ventricular cardiomyocytes (9) . Oxylipins derived from other PUFA also have effects on the heart, such as EPA-derived 18-hydroxy-eicosapentaenoic acid , which is anti-inflammatory in cardiac fibroblasts (10) , and DHA-derived 13,14-epoxydocosapentaenoic acid (13,14-EpDPE), which potently dilates porcine coronary microvessels (11) .…”