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P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

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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.

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Acknowledgments

Research support from the Intramural Research Program of the NIH, NIDDK is acknowledged.

This work was supported in part by Israel Science Foundation grant no. 1352/09. The sponsors were not involved in any way in the making of this paper or the decision to submit it for publication.

Conflicts of interest

None.

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Authors and Affiliations

  1. The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 52900, Israel

    Ronit Cohen, Anna Maksin, Ahuva Isak & Asher Shainberg

  2. Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petach Tikva, Israel

    Edith Hochhauser, Ronit Cohen, Maayan Waldman & Dan Aravot

  3. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0810, USA

    P. Suresh Jayasekara & Kenneth A. Jacobson

  4. Pharma Center Bonn, Pharmaceutical Chemistry I, Pharmaceutical Institute, An der Immenburg 4, 53121, Bonn, Germany

    Christa E. Müller

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  1. Edith Hochhauser
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Correspondence to Asher Shainberg.

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Hochhauser, E., Cohen, R., Waldman, M. et al. P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo. Purinergic Signalling 9, 633–642 (2013). https://doi.org/10.1007/s11302-013-9374-3

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