title: P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo.
abstract: Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y2 and P2Y4 (UTP-activated), P2Y6, and P2Y14. Previously, we showed that uridine 5'-triphosphate (UTP) activating P2Y2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y2R in vitro and in vivo following MI using uridine-5'-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y2R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y2R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0 ± 3.1 % vs. 33.4 ± 2.7 %, p < 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage (p < 0.05) and c-Jun phosphorylation increased. Thus, P2Y2R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo.
authors.affiliation: Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petach Tikva, Israel.
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.forename: Ronit
authors.initials: R
authors.lastname: Cohen
authors.forename: Maayan
authors.initials: M
authors.lastname: Waldman
authors.forename: Anna
authors.initials: A
authors.lastname: Maksin
authors.forename: Ahuva
authors.initials: A
authors.lastname: Isak
authors.forename: Dan
authors.initials: D
authors.lastname: Aravot
authors.forename: P Suresh
authors.initials: PS
authors.lastname: Jayasekara
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058912:Purinergic P2Y Receptor Agonists / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D058912:Purinergic P2Y Receptor Agonists; D058473:Receptors, Purinergic P2Y2