Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats
Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats
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DOI：
10.1291/hypres.29.57
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发表时间：
2006-01-01
影响因子：
5.4
通讯作者：
Komeda, M
中科院分区：
文献类型：
--
作者：
Kanemitsu, H;Takai, S;Komeda, M
人食糜酶不仅激活血管紧张素11，还激活转化生长因子-β（心肌纤维化的主要刺激物），而大鼠食糜酶激活转化生长因子-β，但不激活血管紧张素1f。为了阐明食糜酶依赖性转化生长因子-β激活的作用，我们评估了食糜酶抑制是否可以预防大鼠心肌梗死后的心脏纤维化和心功能障碍。通过结扎左冠状动脉前降支诱发心肌梗塞。结扎一天后，将大鼠随机分为 2 组：1）食糜酶治疗组，每天口服 10 mg/kg 食糜酶抑制剂 NK3201，持续 4 周； 2) 未经治疗的心肌梗塞大鼠载体组。我们还纳入了一个接受假手术且不接受任何治疗的对照组。结扎后四周，超声心动图显示，食糜酶抑制剂治疗减少了运动面积，增加了面积变化分数，但没有显着改变左心室舒张末期面积。食糜酶抑制显着降低左心室舒张末压，增加最大收缩末压-容积关系，并降低左心室舒张时间常数。在载体组中，非梗塞心肌中的食糜酶活性显着增加，但通过食糜酶抑制剂治疗显着降低。食糜酶抑制剂治疗组的心脏组织纤维化面积以及胶原蛋白 I 和胶原蛋白 III 的 mRNA 水平也显着低于媒介物组。因此，形成食糜酶依赖性转化生长因子-β的途径可能在心肌纤维化和心功能障碍中发挥重要作用，而不是心肌梗死后的左心室扩张。
Human chymase activates not only angiotensin 11 but also transforming growth factor-beta, a major stimulator of myocardial fibrosis, while rat chymase activates transforming growth factor-beta, but not angiotensin If. To clarify the role of chymase-dependent transforming growth factor-beta activation, we evaluated whether chymase inhibition prevents cardiac fibrosis and cardiac dysfunction after myocardial infarction in rats. Myocardial infarction was induced by ligation of the left anterior descending coronary artery. One day after the ligation, rats were randomized into 2 groups: 1) a chymase-treated group that received 10 mg/kg per day of the chymase inhibitor NK3201 orally for 4 weeks; and 2) a vehicle group of non-treated rats with myocardial infarction. We also included a control group who underwent sham-operation and no treatment. Four weeks after ligation, echocardiography revealed that chymase inhibitor treatment reduced the akinetic area and increased fractional area change but did not significantly change left ventricular end-diastolic area. Chymase inhibition significantly reduced left ventricular end-diastolic pressure, increased the maximal end-systolic pressure-volume relationship and decreased the time constant of left ventricular relaxation. Chymase activity in the non-infarcted myocardium was significantly increased in the vehicle group, but it was significantly reduced by chymase inhibitor treatment. The fibrotic area in the cardiac tissues and the mRNA levels of collagen I and collagen III were also significantly lower in the chymase inhibitor-treated group than in the vehicle group. Therefore, the pathway forming chymase-dependent transforming growth factor-beta may play an important role in myocardial fibrosis and cardiac dysfunction rather than left ventricular dilatation after myocardial infarction.