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Research ArticleCardiovascular

Characterization of Stressed Transgenic Mice Overexpressing H2-Histamine Receptors in the Heart

Ulrich Gergs, Uwe Kirchhefer, Fabian Bergmann, Bernhard Künstler, Natascha Mißlinger, Bastian Au, Mareen Mahnkopf, Hartmut Wache and Joachim Neumann
Journal of Pharmacology and Experimental Therapeutics September 2020, 374 (3) 479-488; DOI: https://doi.org/10.1124/jpet.120.000063
Ulrich Gergs
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Uwe Kirchhefer
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Fabian Bergmann
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Bernhard Künstler
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Natascha Mißlinger
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Bastian Au
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Mareen Mahnkopf
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Hartmut Wache
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Joachim Neumann
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (U.G., F.B., B.K., N.M., B.A., M.M., H.W., J.N.) and Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany (U.K.)
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Abstract

We studied transgenic mice with cardiac-specific overexpression of H2-histamine receptors (H2-TG) by using the α-myosin heavy-chain promoter. We wanted to address whether this overexpression would protect the heart against paradigmatic stressors. To this end, we studied isolated atrial preparations in an organ bath under normoxic and hypoxic conditions and after prolonged exposure to high histamine concentrations. Moreover, we assessed cardiac function using echocardiography in mice with cardiac hypertrophy due to overexpression of the catalytic subunit of PP2A (PP2A-TG) in the heart [H2-TG × PP2A-TG = double transgenic (DT)] or H2-TG with cardiac systolic failure due to treatment of mice with lipopolysaccharides (LPSs). Furthermore, the effect of ischemia and reperfusion was studied in isolated perfused hearts (Langendorff mode) of H2-TG. We detected evidence for the protective role of the overexpressed H2-histamine receptors in the contractile dysfunction of DT and isolated atrial preparations subjected to hypoxia. In contrast, we noted the detrimental role of H2-histamine receptor overexpression against ischemia (Langendorff perfusion) and LPS-induced systolic heart failure. Hence, the role of H2-histamine receptors in the heart is context-sensitive: the results differ between hypoxia (in atrium) and ischemia (perfused whole heart), as well as between genetically induced hypertrophy (DT) and toxin-induced heart failure (LPS). The underlying molecular mechanisms for the protective or detrimental roles of H2-histamine receptor overexpression in the mammalian heart remain to be elucidated.

SIGNIFICANCE STATEMENT The beneficial and detrimental effects of the cardiac effects of H2-histamine receptors in the heart under stressful conditions, here intended to mimic clinical situations, were studied. The data suggest that depending on the clinically underlying cardiac pathophysiological mechanisms, H2-histamine agonists or H2-histamine antagonists might merit further research efforts to improve clinical drug therapy.

Footnotes

    • Received April 23, 2020.
    • Accepted June 16, 2020.
  • https://doi.org/10.1124/jpet.120.000063.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 3
1 Sep 2020
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Research ArticleCardiovascular

H2 Receptor Expression and Cardiac Stress

Ulrich Gergs, Uwe Kirchhefer, Fabian Bergmann, Bernhard Künstler, Natascha Mißlinger, Bastian Au, Mareen Mahnkopf, Hartmut Wache and Joachim Neumann
Journal of Pharmacology and Experimental Therapeutics September 1, 2020, 374 (3) 479-488; DOI: https://doi.org/10.1124/jpet.120.000063

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Research ArticleCardiovascular

H2 Receptor Expression and Cardiac Stress

Ulrich Gergs, Uwe Kirchhefer, Fabian Bergmann, Bernhard Künstler, Natascha Mißlinger, Bastian Au, Mareen Mahnkopf, Hartmut Wache and Joachim Neumann
Journal of Pharmacology and Experimental Therapeutics September 1, 2020, 374 (3) 479-488; DOI: https://doi.org/10.1124/jpet.120.000063
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