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.).
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.)
J Pharmacol Exp Ther. 2021 Feb;376(2):213-221. doi: 10.1124/jpet.120.000325. Epub 2020 Nov 5.
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, [Pro, D-Ala] 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.
鼠类肥大细胞蛋白酶 4（mMCP-4）是人类糜蛋白酶的功能类似物，是一种在肥大细胞分泌颗粒中合成和储存的丝氨酸蛋白酶。我们之前的研究报告了 mMCP-4 在血管活性肽内皮素-1（ET-1）从其前体大内皮素-1（big ET-1）的成熟和合成中的生理和病理作用。本研究旨在探讨肥大细胞脱颗粒或稳定化对 big ET-1 或血管紧张素 I（Ang I）给药后 mMCP-4 依赖性升压反应的影响。在麻醉小鼠中，化合物 48/80（C48/80）诱导的肥大细胞脱颗粒或 cromolyn 稳定化分别以糜蛋白酶抑制剂（TY-51469）敏感的方式增强或抑制野生型（WT）小鼠中 big ET-1 的剂量依赖性血管加压反应，但在 mMCP-4 敲除小鼠中则不然。此外，用 C48/80 或 cromolyn 预处理的小鼠腹膜肥大细胞中，mMCP-4 依赖性水解荧光底物 Suc-Leu-Leu-Val-Tyr-7-氨基-4-甲基香豆素被耗尽或增强。此外，C48/80 或 cromolyn 分别显著增加或消除 WT 小鼠腹膜液分离的肥大细胞中外源 big ET-1 中 ET-1（1-31）的转化，体外最后，Ang I 的升压反应不受肥大细胞激活或稳定化的影响，而血管紧张素转化酶抗性 Ang I 类似物[Pro，D-Ala]Ang I 诱导的升压反应则被 C48/80 增强。总之，本研究表明，肥大细胞激活增强了 big ET-1 的 mMCP-4 依赖性血管活性，但在小鼠模型中对 Ang I 没有影响。意义陈述：本工作表明，肥大细胞稳定性在大内皮素-1的心血管药理学中发挥重要作用，但在鼠类全身循环中的血管紧张素 I 中则没有。
