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Research ArticleCardiovascular

Histamine H4-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase Cε-Dependent Aldehyde Dehydrogenase Type-2 Activation

Silvia Aldi, Ken-ichi Takano, Kengo Tomita, Kenichiro Koda, Noel Y.-K. Chan, Alice Marino, Mariselis Salazar-Rodriguez, Robin L. Thurmond and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics June 2014, 349 (3) 508-517; DOI: https://doi.org/10.1124/jpet.114.214122
Silvia Aldi
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Ken-ichi Takano
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Kengo Tomita
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Kenichiro Koda
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Noel Y.-K. Chan
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Alice Marino
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Mariselis Salazar-Rodriguez
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Robin L. Thurmond
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Roberto Levi
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.)
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Abstract

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype–ε (PKCε)–aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow–derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.

Footnotes

    • Received February 19, 2014.
    • Accepted March 28, 2014.
  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL034215 and HL47073]; and by the American Heart Association [Grant-in-Aid 11GRNT5600025]; M.S.-R. was supported in part by Central University of Venezuela [Grant CDCH B-09-11-3999-2005]; and N.Y.-K.C. was supported in part by a Pharmaceutical Research and Manufacturers of America Foundation predoctoral fellowship.

  • dx.doi.org/10.1124/jpet.114.214122.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 3
1 Jun 2014
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Research ArticleCardiovascular

H4R Inhibit Mast Cell Renin Release

Silvia Aldi, Ken-ichi Takano, Kengo Tomita, Kenichiro Koda, Noel Y.-K. Chan, Alice Marino, Mariselis Salazar-Rodriguez, Robin L. Thurmond and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 508-517; DOI: https://doi.org/10.1124/jpet.114.214122

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Research ArticleCardiovascular

H4R Inhibit Mast Cell Renin Release

Silvia Aldi, Ken-ichi Takano, Kengo Tomita, Kenichiro Koda, Noel Y.-K. Chan, Alice Marino, Mariselis Salazar-Rodriguez, Robin L. Thurmond and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 508-517; DOI: https://doi.org/10.1124/jpet.114.214122
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