title: Loss of mouse P2Y4 nucleotide receptor protects against myocardial infarction through endothelin-1 downregulation.
abstract: Nucleotides are released in the heart under pathological conditions, but little is known about their contribution to cardiac inflammation. The present study defines the P2Y4 nucleotide receptor, expressed on cardiac microvascular endothelial cells and involved in postnatal heart development, as an important regulator of the inflammatory response to cardiac ischemia. P2Y4-null mice displayed smaller infarcts in the left descending artery ligation model, as well as reduced neutrophil infiltration and fibrosis. Gene profiling identified inter alia endothelin-1 (ET-1) as one of the target genes of P2Y4 in ischemic heart. The reduced level of ET-1 was correlated with reduction of microvascular hyperpermeability, neutrophil infiltration, and endothelial adhesion molecule expression, and it could be explained by the decreased number of endothelial cells in P2Y4-null mice. Expression analysis of metalloproteinases and their tissue inhibitors in ischemic heart revealed reduced expression of matrix metalloproteinase (MMP)-9, reported to be potentially regulated by ET-1, and MMP-8, considered as neutrophil collagenase, as well as reduction of tissue inhibitor of MMP-1 and tissue inhibitor of MMP-4 in P2Y4-null mice. Reduction of cardiac permeability and neutrophil infiltration was also observed in P2Y4-null mice in LPS-induced inflammation model. Protection against infarction resulting from loss of P2Y4 brings new therapeutic perspectives for cardiac ischemia and remodeling.
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1070 Brussels, Belgium;
authors.forename: Michael
authors.initials: M
authors.lastname: Horckmans
authors.affiliation: Unité de Pharmacologie et de Thérapeutique, Université Catholique de Louvain, 1200 Brussels, Belgium;
authors.forename: Hrag
authors.initials: H
authors.lastname: Esfahani
authors.affiliation: Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium;
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1070 Brussels, Belgium;
authors.forename: Sophie
authors.initials: S
authors.lastname: Clouet
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1070 Brussels, Belgium;
authors.forename: Larissa
authors.initials: L
authors.lastname: di Pietrantonio
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 6041 Gosselies, Belgium; and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.affiliation: Unité de Pharmacologie et de Thérapeutique, Université Catholique de Louvain, 1200 Brussels, Belgium;
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1070 Brussels, Belgium; Département de Médecine de Laboratoire, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.affiliation: Unité de Pharmacologie et de Thérapeutique, Université Catholique de Louvain, 1200 Brussels, Belgium;
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1070 Brussels, Belgium; communid@ulb.ac.be.
authors.forename: Didier
authors.initials: D
authors.lastname: Communi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D019332:Endothelin-1 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D018048:Receptors, Purinergic P2 / Q000172:deficiency*; D059467:Transcriptome
chemical_list: D019332:Endothelin-1; D018048:Receptors, Purinergic P2; C104749:purinoceptor P2Y4