Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure
Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure
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DOI：
10.1016/s0022-2828(02)00278-x
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发表时间：
2003-01-01
影响因子：
5
通讯作者：
Makino, N
中科院分区：
文献类型：
--
作者：
Satoh, S;Ueda, Y;Makino, N
Gq-RhoA-Rho激酶通路由神经激素因子如血管紧张素II（Ang II）激活，已被认为是参与左心室（LV）肥大进展为心力衰竭的重要信号通路之一。我们测试了Rho激酶的慢性抑制阻止这一过程的假设。心力衰竭诱导达尔盐敏感（DS）大鼠喂食8%NaCl饮食从8至17周龄。Y-27632（5 mg/kg/天）是一种选择性Rho激酶抑制剂，从10周龄开始经口给予DS大鼠7周（DS/Y+）。不含Y-27632的DS大鼠（DS/Y-）和喂食8%NaCl饲料的Dahl耐盐（DR）大鼠分别被视为非治疗对照和血压正常对照。在17周龄时，DS/Y-和DS/Y+大鼠的血压没有显著差异。DS/Y-大鼠表现出：（2）收缩功能障碍，即LV射血分数和缩短分数%降低，以及离体乳头肌的抽搐收缩中达到峰值张力以及达到50%松弛的时间延长;（3）心肌细胞膜部分Gaq和Rho激酶蛋白表达增加。在DS/Y+大鼠中，心肌肥大的程度被显著抑制，与改善的收缩功能相关，而不降低间质纤维化的程度。我们的研究结果表明，Gq-Rho激酶通路在高血压诱导的左室肥厚导致收缩功能障碍的过程中起着重要作用的可能性。(C)2003爱思唯尔科技有限公司版权所有。
The Gq-RhoA-Rho kinase pathway, activated by neurohormonal factors such as angiotensin II (Ang II), has been proposed to be one of the important signaling pathways involved in the progression of left ventricular (LV) hypertrophy to heart failure. We tested the hypothesis that chronic inhibition of Rho kinase prevents this process. Heart failure was induced in Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from 8 until 17 weeks of age. Y-27632 (5 mg/kg per day), a selective Rho kinase inhibitor, was applied orally to DS rats starting at 10 weeks of age for 7 weeks (DS/Y+). DS rats without Y-27632 (DS/Y-) and Dahl salt-resistant (DR) rats fed the 8% NaCl diet were regarded as non-therapeutic and normotensive controls, respectively. At 17 weeks of age, there was no significant difference in the blood pressure of DS/Y- and DS/Y+ rats. DS/Y- rats exhibited: (1) increases in LV mass, cross-sectional area (CSA) of cardiomyocytes, and interstitial fibrosis; (2) contractile dysfunction, i.e. decreases in LV ejection fraction and % fractional shortening, and prolongation of time to peak tension as well as to 50% relaxation in the twitch contraction of isolated papillary muscle; and (3) increases in the protein expression of Gaq and Rho kinase in the myocardial membrane fraction. In DS/Y+ rats, the degree of myocardial hypertrophy was significantly inhibited in association with improved contractile function, without a decrease in the degree of interstitial fibrosis. Our results suggest the possibility that the Gq-Rho kinase pathway plays an important role in the process of hypertension-induced LV hypertrophy leading to contractile dysfunction. (C) 2003 Elsevier Science Ltd. All rights reserved.