Palaniyandi Suresh S, Nagai Yusuke, Watanabe Kenichi, Ma Meilei, Veeraveedu Punniyakoti T, Prakash Paras, Kamal Fadia A, Abe Yuichi, Yamaguchi Ken'ichi, Tachikawa Hitoshi, Kodama Makoto, Aizawa Yoshifusa
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, 956-8603, Japan.
Exp Biol Med (Maywood). 2007 Oct;232(9):1213-21. doi: 10.3181/0703-RM-85.
Chymase has been known as a local angiotensin II-generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-beta1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-beta1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.
在犬、猴、仓鼠和人类的心血管系统中，糜酶一直被认为是一种局部生成血管紧张素II的酶；然而，最近有报道称糜酶还具有多种其他功能。因此，我们决定研究抑制糜酶是否能改善与大鼠扩张型心肌病病理生理学相关的疾病状况，以及其可能的作用机制，因为大鼠糜酶无法产生血管紧张素II。我们研究了新型糜酶抑制剂TY - 51469（0.1毫克/千克/天[CYI - 0.1组，n = 15]和1毫克/千克/天[CYI - 1组，n = 15]）对肌球蛋白免疫后心肌炎大鼠的影响。另一组肌球蛋白免疫大鼠接受赋形剂治疗（V组，n = 15）。未免疫的年龄匹配正常大鼠（N组，n = 10）也纳入了研究。治疗4周后，我们评估了心脏功能、纤维化面积、纤维生成、转化生长因子（TGF）-β1和III型胶原蛋白水平、肥大及其标志物心房利钠肽（ANP）以及肥大细胞活性。肌球蛋白免疫后，用糜酶抑制剂治疗，存活率和心肌功能呈剂量依赖性改善。在接受糜酶抑制剂治疗的心肌炎后大鼠中，观察到心肌纤维化面积百分比、纤维生成、心肌肥大和肥大细胞活性降低，同时心肌中TGF -β1、III型胶原蛋白和ANP水平也降低。该治疗还降低了这些动物的心肌醛固酮合酶水平。抑制糜酶可通过防止大鼠的病理重塑和残留炎症，减轻心肌炎后扩张型心肌病的发病机制并延缓向心力衰竭的进展。
