Endothelin-1 Is Involved in Mechanical Stress-induced Cardiomyocyte Hypertrophy (*)
- Tsutomu Yamazaki(1)(2),
- Issei Komuro(1)(§),
- Sumiyo Kudoh(1),
- Yunzeng Zou(1),
- Ichiro Shiojima(1),
- Yukio Hiroi(1),
- Takehiko Mizuno(1),
- Koji Maemura(1),
- Hiroki Kurihara(1),
- Ryuichi Aikawa(1),
- Hiroyuki Takano(1) and
- Yoshio Yazaki(1)
- From the (1)Third Department of Internal Medicine, University of Tokyo School of Medicine and the
- (2)Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
- §To whom correspondence should be addressed. Tel.: 81-3-3815-5411 (ext. 3127); Fax: 81-3-3815-2087; :komuro-tky{at}umin.u-tokyo.ac.jp.
Abstract
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
10
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 
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.
Footnotes
-
↵* This work was supported by a grant-in-aid for scientific research and developmental scientific research from the Ministry of Education, Science, Sports, and Culture of Japan, a grant from the Japan Cardiovascular Foundation and the Sankyo Life Science and Study Group of Molecular Cardiology, Japan (to I. K.), and Japan Heart Foundation Research Grant for 1994 (to T. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- Raf-1
-
Raf-1 kinase
- MAP
-
mitogen-activated protein
- ATII
-
angiotensin II
- ET-1
-
endothelin-1
- ET
-
endothelin-1 type A
- ET
-
endothelin-1 type B
- MBP
-
myelin basic protein.
-
- Received August 24, 1995.
- Revision received December 1, 1995.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
