title: Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor.
abstract: Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously, we reported that cardiomyocyte-specific EP4 knockout mice develop dilated cardiomyopathy with reduced ejection fraction. Thus, we hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3.
  
  
  
  The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse Langendorff preparation and in adult mouse cardiomyocytes. Isolated hearts of adult male C57Bl/6 mice were perfused with PGE2 (10(-6) M) or sulprostone (10(-6) M) and compared with vehicle. Both PGE2 and sulprostone decreased +dp/dt (P<0.01) and left ventricular developed pressure (P<0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. Adult mouse cardiomyocytes contractility was also reduced after treatment with either PGE2 or sulprostone for 10 minutes. We then examined the acute effects of PGE2, sulprostone, and the EP4 agonist on expression of phosphorylated phospholamban and sarcoendoplasmic reticulum Ca(2+)-ATPase 2a in adult mouse cardiomyocytes using Western blot. Treatment with either PGE2 or sulprostone decreased expression of phosphorylated phospholamban corrected to total phospholamban, whereas treatment with the EP4 agonist had the opposite effect. Sarcoendoplasmic reticulum Ca(2+)-ATPase 2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure-volume loops. Both PGE2 and sulprostone decreased +dp/dt, whereas the EP4 agonist increased +dp/dt.
  
  
  
  Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in phospholamban phosphorylation and has relevance to detrimental effects of inflammation.
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.).
authors: Xiaosong
authors: X
authors: Gu
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.).
authors: Jiang
authors: J
authors: Xu
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.).
authors: Liping
authors: L
authors: Zhu
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.).
authors: Timothy
authors: T
authors: Bryson
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.).
authors: Xiao-Ping
authors: XP
authors: Yang
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.).
authors: Edward
authors: E
authors: Peterson
authors: From the Hypertension and Vascular Research Division, Department of Internal Medicine (X.G., J.X., L.Z., T.B., X.-P.Y., P.H.) and Department of Physiology (T.B., P.H.), Wayne State University School of Medicine, Detroit, MI; Department of Public Health Sciences (E.P.), Henry Ford Hospital, Detroit, MI; and Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (X.G.). phardin1@hfhs.org.
authors: Pamela
authors: P
authors: Harding
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000067268:Isolated Heart Preparation; D008297:Male; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D015232:Dinoprostone; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C545648:Ptger3 protein, mouse; C545651:Ptger4 protein, mouse; C016767:sulprostone; C506947:Atp2a2 protein, mouse
keywords: cardiomyopathy, dilated; heart contractility; inflammation; phospholamban; prostaglandin E2