The role of endothelin-converting enzyme-1 in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes.
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 alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes.


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 beta-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 alpha1-adrenergic-stimulated hypertrophy and beta-myosin heavy chain gene transcription.
Kaburagi
S
S
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hasegawa
K
K
Morimoto
T
T
Araki
M
M
Sawamura
T
T
Masaki
T
T
Sasayama
S
S
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002478:Cells, Cultured; D006224:Cricetinae; D019332:Endothelin-1 / Q000096:biosynthesis*; D000072396:Endothelin-Converting Enzymes; D006984:Hypertrophy; D008647:Mesocricetus; D008666:Metalloendopeptidases; D009206:Myocardium / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013754:Tetracyclines / Q000494:pharmacology; D014158:Transcription, Genetic
D000316:Adrenergic alpha-Agonists; D019332:Endothelin-1; D012333:RNA, Messenger; D013754:Tetracyclines; C088494:WS 79089B; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D018995:Myosin Heavy Chains