title: Crucial role of phospholamban phosphorylation and S-nitrosylation in the negative lusitropism induced by 17β-estradiol in the male rat heart.
abstract: OBJECTIVE
  17β-estradiol (17βE2) plays an important cardiovascular role by activating estrogen receptors (ER) α and ERβ. Previous studies demonstrated that the novel estrogen G protein-coupled receptor (GPR30/GPER) mediates estrogen action in different tissues. We have recently shown in the rat heart that 17βE2 elicits negative inotropism through ERα, ERβ and GPR30, by triggering activation of ERK1/2, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA) and endothelial Nitric Oxide synthase (eNOS) signaling.
  
  
  METHODS
  In the present study, using the isolated and Langendorff-perfused rat heart as a model system we analyzed: i) whether and to which extent 17βE2 modifies mammalian ventricular myocardial relaxation (lusitropism); ii) the type of ERs and the signaling pathways involved in this effect.
  
  
  RESULTS
  We found that 17βE2 negatively modulated the ventricular lusitropic performance. This effect, which partially involved the vascular endothelium, recruited ERβ and occurred via PI3K, eNOS-NO-cGMP-protein kinase G (PKG) transduction cascade. Of note, 17βE2-mediated negative lusitropism associated with a modification of phospholamban (PLN) phosphorylation and S-nitrosylation (SNO) both in isolated Langendorff rat heart and in isolated cardiomyocytes.
  
  
  CONCLUSIONS
  Taken together, our results allow including 17βE2 to the family of substances that control ventricular relaxation. This is of relevance in relation not only to the normal endocrine control of cardiac function, but also to physio-pathologic conditions characterized by an altered ventricular diastolic performance.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Filice
authors.forename: Tommaso
authors.initials: T
authors.lastname: Angelone
authors.forename: Ernestina M
authors.initials: EM
authors.lastname: De Francesco
authors.forename: Daniela
authors.initials: D
authors.lastname: Pellegrino
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cerra
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D017869:Cyclic GMP-Dependent Protein Kinases; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000099211:Phospholamban