Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II - Induced cardiac hypertrophy and remodeling
Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II - Induced cardiac hypertrophy and remodeling
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DOI：
10.1161/01.res.0000100665.67510.f5
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发表时间：
2003-10-31
影响因子：
20.1
通讯作者：
Iwao, H
中科院分区：
文献类型：
--
作者：
Izumiya, Y;Kim, S;Iwao, H
多项证据表明，血管紧张素 II (Ang II) 不仅会诱发高血压，还会直接导致心脏病。细胞凋亡信号调节激酶 1 (ASK1) 是丝裂原激活蛋白激酶激酶之一，在应激诱导的细胞反应中发挥着关键作用。然而，对于 ASK1 在体内心脏肥大和重塑中的作用尚不清楚。在本研究中，我们通过使用ASK1缺陷小鼠（ASK1(-/-)小鼠），研究了ASK1在Ang II诱导的心脏肥大和重构中的作用。在野生型小鼠中，左心室 (LV) ASK1 被 Ang II 输注激活，这是由血管紧张素 II 1 型受体和超氧化物介导的。尽管Ang II诱导的高血压作用与野生型和ASK1(-/-)小鼠相当，但在ASK1(-/-)小鼠中未检测到Ang II对LV ASK1的激活，并且ASK(-/-)小鼠中p38和c-Jun N末端激酶(JNK)的激活少于野生型小鼠。 ASK1(-/-) 和野生型小鼠之间连续输注 Ang II 引起的血压升高相当。然而，与野生型小鼠相比，Ang II诱导的心脏肥大和重塑，包括心肌细胞肥大、心脏肥大相关mRNA上调、心肌细胞凋亡、间质纤维化、冠状动脉重塑和胶原基因上调，在ASK1(-/-)小鼠中显着减弱。这些结果提供了第一个体内证据，证明 ASK1 是 Ang II 诱导的心脏肥大和重塑的关键信号分子。因此，ASK1被认为是心脏病的潜在治疗靶点。
Multiple lines of evidence establish that angiotensin II (Ang II) induces not only hypertension but also directly contributes to cardiac diseases. Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in stress-induced cellular responses. However, nothing is known about the role of ASK1 in cardiac hypertrophy and remodeling in vivo. In this study, by using mice deficient in ASK1 (ASK1(-/-) mice), we investigated the role of ASK1 in cardiac hypertrophy and remodeling induced by Ang II. Left ventricular (LV) ASK1 was activated by Ang II infusion in wild-type mice, which was mediated by angiotensin II type 1 receptor and superoxide. Although Ang II-induced hypertensive effect was comparable to wild-type and ASK1(-/-) mice, LV ASK1 activation by Ang II was not detectable in ASK1(-/-) mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesser in ASK(-/-) mice than in wild-type mice. Elevation of blood pressure by continuous Ang II infusion was comparable between ASK1(-/-) and wild-type mice. However, Ang II-induced cardiac hypertrophy and remodeling, including cardiomyocyte hypertrophy, cardiac hypertrophy-related mRNA upregulation, cardiomyocyte apoptosis, interstitial fibrosis, coronary arterial remodeling, and collagen gene upregulation, was significantly attenuated in ASK1(-/-) mice compared with wild-type mice. These results provided the first in vivo evidence that ASK1 is the critical signaling molecule for Ang II-induced cardiac hypertrophy and remodeling. Thus, ASK1 is proposed to be a potential therapeutic target for cardiac diseases.