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Research ArticleCardiovascular

Mast Cell Degranulation Increases Mouse Mast Cell Protease 4–Dependent Vasopressor Responses to Big Endothelin-1 But Not Angiotensin I

Laurence Vincent, Catherine Lapointe, Modou Lo, Hugo Gagnon, Gunnar Pejler, Shinji Takai, Robert Day and Pedro D’Orléans-Juste
Journal of Pharmacology and Experimental Therapeutics February 2021, 376 (2) 213-221; DOI: https://doi.org/10.1124/jpet.120.000325
Laurence Vincent
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Catherine Lapointe
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Modou Lo
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Hugo Gagnon
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Gunnar Pejler
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Shinji Takai
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Robert Day
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Pedro D’Orléans-Juste
Department of Pharmacology and Physiology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada (L.V., C.L., M.L., P.D.-J.); PhenoSwitch Bioscience Inc., Sherbrooke, Quebec, Canada (H.G.); Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden (G.P.); Department of Innovative Medicine, Osaka Medical College, Osaka, Japan (S.T.); and Department of Surgery, Division of Urology, Université de Sherbrooke, Sherbrooke, Quebec, Canada (R.D.)
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Abstract

Mouse mast cell protease 4 (mMCP-4), the murine functional analog to the human chymase, is a serine protease synthesized and stored in mast cell secretory granules. Our previous studies reported physiologic and pathologic roles for mMCP-4 in the maturation and synthesis of the vasoactive peptide endothelin-1 (ET-1) from its precursor, big ET-1. The aim of this study was to investigate the impact of mast cell degranulation or stabilization on mMCP-4–dependent pressor responses after the administration of big ET-1 or angiotensin I (Ang I). In anesthetized mice, mast cell degranulation induced by compound 48/80 (C48/80) or stabilization by cromolyn enhanced or repressed, respectively, the dose-dependent vasopressor responses to big ET-1 in wild-type (WT) mice but not in mMCP-4 knockout mice in a chymase inhibitor (TY-51469)–sensitive fashion. In addition, mMCP-4–dependent hydrolysis of the fluorogenic substrate Suc-Leu-Leu-Val-Tyr–7-amino-4-methylcoumarin was depleted or enhanced in peritoneal mast cells isolated from mice pretreated with C48/80 or cromolyn, respectively. Furthermore, C48/80 or cromolyn markedly increased or abolished, respectively, ET-1 (1–31) conversion from exogenous big ET-1 in WT mice peritoneal fluid–isolated mast cells, in vitro. Finally, the vasopressor responses to Ang I were unaffected by mast cell activation or stabilization, whereas those induced by the angiotensin-converting enzyme-resistant Ang I analog, [Pro11, D-Ala12] Ang I, were potentiated by C48/80. Altogether, the present study shows that mast cell activation enhances the mMCP-4–dependent vasoactive properties of big ET-1 but not Ang I in the mouse model.

SIGNIFICANCE STATEMENT The current work demonstrates a significant role for mast cell stability in the cardiovascular pharmacology of big endothelin-1 but not angiotensin I in the murine systemic circulation.

Footnotes

    • Received September 7, 2020.
    • Accepted November 2, 2020.
  • This project was financially supported by the Canadian Institutes for Health Research (MOP-57883) and le Réseau Québecois de Recherche sur le Médicament (Fonds de Recherche Santé, Québec). P.D.-J. is the recipient of a Joseph C. Edwards Cardiology Chair. C.L. is the recipient of a doctorate studentship from the Université de Sherbrooke.

  • https://doi.org/10.1124/jpet.120.000325.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleCardiovascular

Mast Cell Degranulation Enhances Big ET-1 Pressor Response

Laurence Vincent, Catherine Lapointe, Modou Lo, Hugo Gagnon, Gunnar Pejler, Shinji Takai, Robert Day and Pedro D’Orléans-Juste
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 213-221; DOI: https://doi.org/10.1124/jpet.120.000325

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Research ArticleCardiovascular

Mast Cell Degranulation Enhances Big ET-1 Pressor Response

Laurence Vincent, Catherine Lapointe, Modou Lo, Hugo Gagnon, Gunnar Pejler, Shinji Takai, Robert Day and Pedro D’Orléans-Juste
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 213-221; DOI: https://doi.org/10.1124/jpet.120.000325
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