ACTIVATION OF ANGIOTENSIN-II FORMING CHYMASE IN THE CARDIOMYOPATHIC HAMSTER HEART

Background Angiotensin (ANG) II plays crucial roles in promoting cardi ovascular tissue remodeling, Human chymase catalyzes ANG II formation, whereas rat chymase (rat mast cell protease I) degrades ANG I to inac tive fragments, Such species differences should be considered when the functions of chymase in human cardiovascular diseases are investigate d assuming an analogy with animal models. Objective To further charact erize the recently identified ANG It-forming hamster chymase, and to a nalyze pathophysiologic roles played by chymase in the cardiomyopathy of the hamster. Methods The gene organization and the primary structur e of hamster chymase were determined through molecular cloning, Chymas e and angiotensin converting enzyme messenger RNA levels, and chymase- like and angiotensin converting enzyme activities were measured in the heart of BIO 14,6 cardiomyopathic hamsters aged 4, 12, and 25 weeks, Results The hamster chymase gene is 3 kb long, It has five exons and f our introns, and the deduced amino-acid sequence was homologous to oth er mammalian chymases, The chymase messenger RNA levels and chymase-li ke activities in the BIO 14.6 hamster hearts were increased significan tly at the ages of 12 weeks (the fibrotic stage) and 25 weeks (the hyp ertrophic stage), but not at age 4 weeks (the premyolytic stage), Conc lusions These results indicate that heart chymase is activated concurr ently with the development of cardiomyopathy. Thus, we conclude that h eart chymase could play the primary role in accelerating ANG II format ion, thereby causing deleterious changes in the cardiomyopathic heart.