PT  - JOURNAL ARTICLE
AU  - Martin Houde
AU  - Marc-David Jamain
AU  - Julie Labonté
AU  - Louisane Desbiens
AU  - Gunnar Pejler
AU  - Michael Gurish
AU  - Shinji Takai
AU  - Pedro D'Orléans-Juste
TI  - Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1
AID  - 10.1124/jpet.112.202275
DP  - 2013 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 31--37
VI  - 346
IP  - 1
4099  - http://jpet.aspetjournals.org/content/346/1/31.short
4100  - http://jpet.aspetjournals.org/content/346/1/31.full
SO  - J Pharmacol Exp Ther2013 Jul 01; 346
AB  - The serine protease chymase has been reported to generate intracardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin-1 (ET-1), ET-1 (1–31) from Big-ET-1. Although humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model. Basal mean arterial pressure did not differ between wild-type (WT) and mMCP-4(−/−) mice. Systemic administration of Big-ET-1 triggered pressor responses and increased blood levels of immunoreactive (IR) ET-1 (1–31) and ET-1 that were reduced by more than 50% in mMCP-4 knockout (−/−) mice compared with WT controls. Residual responses to Big-ET-1 in mMCP-4(−/−) mice were insensitive to the enkephalinase/neutral endopeptidase inhibitor thiorphan and the specific chymase inhibitor TY-51469 {2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl]thiazole-4-carboxylic acid}. Soluble fractions from the lungs, left cardiac ventricle, aorta, and kidneys of WT but not mMCP-4(−/−) mice generated ET-1 (1–31) from exogenous Big-ET-1 in a TY-51469-sensitive fashion as detected by high-performance liquid chromatography/ matrix-assisted laser desorption/ionization-mass spectrometry. Finally, pulmonary endogenous levels of IR-ET-1 were reduced by more than 40% in tissues derived from mMCP-4(−/−) mice compared with WT mice. Our results show that mMCP-4 plays a pivotal role in the dynamic conversion of systemic Big-ET-1 to ET-1 in the mouse model.