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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 376; no. 2; pp. 213 - 221
• Main Authors: Vincent, Laurence, Lapointe, Catherine, Lo, Modou, Gagnon, Hugo, Pejler, Gunnar, Takai, Shinji, Day, Robert, D’Orléans-Juste, Pedro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2021
• Subjects: Angiotensin I - pharmacology; Animals; Blood Pressure; Cell Degranulation; Cells, Cultured; Chymases - antagonists & inhibitors; Cromolyn Sodium - pharmacology; Endothelin-1 - pharmacology; Enzyme Inhibitors - pharmacology; Male; Mast Cell Stabilizers - pharmacology; Mast Cells - drug effects; Mast Cells - metabolism; Mast Cells - physiology; Mice; Mice, Inbred C57BL; Peritoneum - cytology; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Sulfonamides - pharmacology; Thiophenes - pharmacology; ACE; Ang I; KO; rmMCP-4; ECE; mMCP-4; HR; C48/80; Ang II; BSA; ET-1; AMC; NEP; MAP; WT
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.120.000325

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. 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.