(Circulation. 1999;99:292-298.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
The Role of Endothelin-Converting Enzyme-1 in the Development of 
1-Adrenergic-Stimulated Hypertrophy in Cultured Neonatal Rat Cardiac Myocytes
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and the Department of Bioscience, National Cardiovascular Research Center, Osaka, Japan (T.S., T. Masaki).
Correspondence to Koji Hasegawa, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin Sakyo-ku, Kyoto, 606-8507 Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp
Background—Accumulating evidence
suggests that the local synthesis of endothelin-1 (ET-1) plays a role
in the development of heart failure in vivo. We investigated the role
of endothelin-converting enzyme-1 (ECE-1), which mediates the
conversion of big ET-1 to mature ET-1, in the development of
1-adrenergic–stimulated hypertrophy in
cultured neonatal rat cardiac myocytes.
Methods and Results—Phenylephrine (PE) induced the expression of ET-1 in rat cardiac myocytes and accelerated the conversion of big ET-1 to ET-1. The ECE-1 mRNA levels were markedly increased 3 hours after PE stimulation (3.6-fold compared with saline stimulation, P<0.005). A specific ECE-1 antagonist, FR901533, inhibited the PE-stimulated increase in protein synthesis rate by 45% (P<0.05). As genetic markers for the hypertrophic response, FR901533 inhibited the PE-stimulated transcriptional activities of the 3.5-kb ß-myosin heavy chain promoter by 79% (P<0.01) but did not affect that of the 3.4-kb atrial natriuretic factor (ANF) promoter. In Bio14.6 Syrian cardiomyopathic hamsters, ventricular ET-1 and ANF mRNA levels did not correlate at 2 different stages.
Conclusions—ET-1-independent pathways may mediate activation of
the ANF gene program in ventricular myocytes
both in vitro and in vivo. These results also indicate that the
conversion of big ET-1 to ET-1 in rat cardiac myocytes is required for
the development of 1-adrenergic-stimulated
hypertrophy and ß-myosin heavy chain gene
transcription.
Key Words: endothelin • cardiac hypertrophy • gene expression
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