Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17 beta-estradiol in the Male Rat Heart

Background/Aims: 17 beta-estradiol (17 beta E2) plays an important cardiovascular role by activating estrogen receptors (ER) alpha and ER beta. 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 17 beta E2 elicits negative inotropism through ER alpha, ER beta 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 17 beta E2 modifies mammalian ventricular myocardial relaxation (lusitropism); ii) the type of ERs and the signaling pathways involved in this effect. Results: We found that 17 beta E2 negatively modulated the ventricular lusitropic performance. This effect, which partially involved the vascular endothelium, recruited ER beta and occurred via PI3K, eNOS-NO-cGMP-protein kinase G (PKG) transduction cascade. Of note, 17 beta E2-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. Conclusion: Taken together, our results allow including 17 beta E2 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. Copyright (C) 2011 S. Karger AG, Basel