Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Hiroi Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Takano H, Yazaki Y
Third Department of Internal Medicine, University of Tokyo School of Medicine and the Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
J Biol Chem. 1996 Feb 9;271(6):3221-8. doi: 10.1074/jbc.271.6.3221.
We have recently shown that mechanical stress induces cardiomyocyte hypertrophy partly through the enhanced secretion of angiotensin II (ATII). Endothelin-1 (ET-1) has been reported to be a potent growth factor for a variety of cells, including cardiomyocytes. In this study, we examined the role of ET-1 in mechanical stress-induced cardiac hypertrophy by using cultured cardiomyocytes of neonatal rats. ET-1 (10(-8) approximately 10(-7) M) maximally induced the activation of both Raf-1 kinase and mitogen-activated protein (MAP) kinases at 4 and 8 min, respectively, followed by an increase in protein synthesis at 24 h. All of these hypertrophic responses were completely blocked by pretreatment with BQ123, an antagonist selective for the ET-1 type A receptor subtype, but not by BQ788, an ET-1 type B receptor-specific antagonist. BQ123 also suppressed stretch-induced activation of MAP kinases and an increase in phenylalanine uptake by approximately 60 and 50%, respectively, but BQ788 did not. ET-1 was constitutively secreted from cultured cardiomyocytes, and a significant increase in ET-1 concentration was observed in the culture medium of cardiomyocytes after stretching for 10 min. After 24 h, an approximately 3-fold increase in ET-1 concentration was observed in the conditioned medium of stretched cardiomyocytes compared with that of unstretched cardiomyocytes. ET-1 mRNA levels were also increased at 30 min after stretching. Moreover, ET-1 and ATII synergistically activated Raf-1 kinase and MAP kinases in cultured cardiomyocytes. In conclusion, mechanical stretching stimulates secretion and production of ET-1 in cultured cardiomyocytes, and vasoconstrictive peptides such as ATII and ET-1 may play an important role in mechanical stress-induced cardiac hypertrophy.
我们最近发现，机械应力部分通过增强血管紧张素II（ATII）的分泌来诱导心肌细胞肥大。内皮素-1（ET-1）据报道是包括心肌细胞在内的多种细胞的强效生长因子。在本研究中，我们使用新生大鼠的培养心肌细胞研究了ET-1在机械应力诱导的心脏肥大中的作用。ET-1（10^(-8) 至10^(-7) M）分别在4分钟和8分钟时最大程度地诱导Raf-1激酶和丝裂原活化蛋白（MAP）激酶的激活，随后在24小时时蛋白质合成增加。所有这些肥大反应均被ET-1 A型受体亚型选择性拮抗剂BQ123预处理完全阻断，但未被ET-1 B型受体特异性拮抗剂BQ788阻断。BQ123还分别抑制拉伸诱导的MAP激酶激活和苯丙氨酸摄取增加约60%和50%，但BQ788没有。ET-1由培养的心肌细胞组成性分泌，拉伸10分钟后心肌细胞培养基中ET-1浓度显著增加。24小时后，与未拉伸的心肌细胞相比，拉伸的心肌细胞条件培养基中ET-1浓度增加约3倍。拉伸后30分钟ET-1 mRNA水平也增加。此外，ET-1和ATII在培养的心肌细胞中协同激活Raf-1激酶和MAP激酶。总之，机械拉伸刺激培养的心肌细胞中ET-1的分泌和产生，血管收缩肽如ATII和ET-1可能在机械应力诱导的心脏肥大中起重要作用。
