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Journal of Pharmacology and Experimental Therapeutics

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OtherCardiovascular

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'Orleans-Juste
Journal of Pharmacology and Experimental Therapeutics November 5, 2020, JPET-AR-2020-000325; DOI: https://doi.org/10.1124/jpet.120.000325
Laurence Vincent
1Pharmacology, Université de Sherbrooke, Canada
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Catherine Lapointe
2Université de Sherbrooke, Canada
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Modou Lo
2Université de Sherbrooke, Canada
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Hugo Gagnon
3Phenoswitch Biosciences, Canada
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Gunnar Pejler
4Uppsala University, Sweden
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Shinji Takai
5University of Osaka, Japan
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Robert Day
2Université de Sherbrooke, Canada
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Pedro D'Orleans-Juste
6Department of Pharmacology, University of Sherbrooke, Canada
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  • For correspondence: labpdj@usherbrooke.ca
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Abstract

Mouse mast cell protease 4 (mMCP-4), the murine functional analogue to the human chymase, is a serine protease synthesized and stored in mast cell secretory granules. Our previous studies reported physiological and pathological roles for mMCP-4 in the maturation and synthesis of the vasoactive peptide endothelin-1 (ET-1) from its precursor, big endothelin-1 (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 following 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 pre-treated 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 analogue, [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 ET-1 but not Ang I in the murine systemic circulation. This study also demonstrate for the first time that an ACE-resistant Ang I analogue is susceptible to chymase-dependent activation in the mouse model.

  • angiotensin
  • animal models
  • blood pressure
  • Endothelin
  • mast cells
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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OtherCardiovascular

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'Orleans-Juste
Journal of Pharmacology and Experimental Therapeutics November 5, 2020, JPET-AR-2020-000325; DOI: https://doi.org/10.1124/jpet.120.000325

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OtherCardiovascular

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'Orleans-Juste
Journal of Pharmacology and Experimental Therapeutics November 5, 2020, JPET-AR-2020-000325; DOI: https://doi.org/10.1124/jpet.120.000325
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