Species differences in angiotensin II generation and degradation by mast cell chymases

Although chymases are known to exhibit species differences in regard to angiotensin (Ang) II generation and degradation, their properties have never been compared under the same experimental conditions. We analyzed the processing of Ang I by chymases of a variety of species (human chymase, dog chymase, hamster chymase-1, rat mast cell protease-1 [rMCP-1], mouse mast cell protease-4 [mMCP-4]) at physiological ionic strength and under neutral pH conditions. Human chymase generated Ang II from Ang I without further degradation, whereas the chymases of other species generated Ang II, followed by degradation at the Tyr(4)-Ile(5) site in a time-dependent manner. Kinetic analysis showed that in terms of Ang II generating activity (analyzed by cleavage of the Phe(8)-His(9) bond using the model peptide Ang(5-10), Ile(5)-His(6)-Pro(7)-Phe(8)-His(9)-Leu(10)), the chymases ranked as follows: dog > human > hamster > mouse > rat (k(cat)/K-m: 18, 11, 0.69, 0.059, 0.030 mu M(-1)min(-1)), and that in terms of Ang II degrading activity (i.e., cleavage of the Tyr(4)-Ile(5) bond of Ang II), the order was hamster > rat > mouse > dog (k(cat)/K-m: 5.4, 4.8, 0.39, 0.29 mu M(-1)min(-1)). These results suggest species differences in the contribution of chymases to local Ang II generation and degradation.