Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine.
The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 micromol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours, P<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of (3)H-phenylalanine (1.4-fold by ET and 1.5-fold by PE, P<0.01), cell size (2.3-fold and 2.5-fold, P<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold, P<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold, P<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of (3)H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.
Omura
Takashi
T
Department of Internal Medicine and Cardiology, Osaka City University Medical School, Osaka, Japan. omura@med.osaka-cu.ac.jp
Yoshiyama
Minoru
M
Yoshida
Ken
K
Nakamura
Yasuhiro
Y
Kim
Shokei
S
Iwao
Hiroshi
H
Takeuchi
Kazuhide
K
Yoshikawa
Junichi
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005799:Genes, Dominant / Q000235:genetics; D016758:Genes, jun / Q000235:genetics*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007763:Lac Operon / Q000235:genetics; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis; D010656:Phenylephrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection
D018076:DNA, Complementary; D019332:Endothelin-1; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D020097:Natriuretic Peptide, Brain; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor