doi: 10.1161/hy0102.100783
(Hypertension. 2002;39:81.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Dominant Negative Mutant of c-Jun Inhibits Cardiomyocyte Hypertrophy Induced by Endothelin 1 and Phenylephrine
From the Department of Internal Medicine and Cardiology (T.O., M.Y., K.Y., Y.N., K.T., J.Y.) and the Department of Pharmacology (S.K., H.I.), Osaka City University Medical School, Osaka, Japan.
Correspondence to Takashi Omura, Department of Internal Medicine and Cardiology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku Osaka 545-8585, Japan. E-mail omura{at}med.osaka-cu.ac.jp
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 µmol/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 3H-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 3H-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.
Key Words: hypertrophy, cardiac • c-Jun • mutation • myocytes
This article has been cited by other articles:
 |
|
 |
|
  B. V. Alvarez, D. E. Johnson, D. Sowah, D. Soliman, P. E. Light, Y. Xia, M. Karmazyn, and J. R. Casey Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy J. Physiol., February 15, 2007; 579(1): 127 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hilfiker-Kleiner, A. Hilfiker, M. Castellazzi, K. C. Wollert, C. Trautwein, H. Schunkert, and H. Drexler JunD attenuates phenylephrine-mediated cardiomyocyte hypertrophy by negatively regulating AP-1 transcriptional activity Cardiovasc Res, July 1, 2006; 71(1): 108 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Enomoto, M Yoshiyama, T Omura, R Matsumoto, T Kusuyama, S Kim, Y Izumi, K Akioka, H Iwao, K Takeuchi, et al. Effects of eplerenone on transcriptional factors and mRNA expression related to cardiac remodelling after myocardial infarction Heart, December 1, 2005; 91(12): 1595 - 1600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hilfiker-Kleiner, A. Hilfiker, K. Kaminski, A. Schaefer, J.-K. Park, K. Michel, A. Quint, M. Yaniv, J. B. Weitzman, and H. Drexler Lack of JunD Promotes Pressure Overload-Induced Apoptosis, Hypertrophic Growth, and Angiogenesis in the Heart Circulation, September 6, 2005; 112(10): 1470 - 1477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Schneiders, J. Heger, P. Best, H. Michael Piper, and G. Taimor SMAD proteins are involved in apoptosis induction in ventricular cardiomyocytes Cardiovasc Res, July 1, 2005; 67(1): 87 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Y. Jeong, K. Kinugawa, C. Vinson, and C. S. Long AFos Dissociates Cardiac Myocyte Hypertrophy and Expression of the Pathological Gene Program Circulation, April 5, 2005; 111(13): 1645 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Omura, M. Yoshiyama, T. Hayashi, S. Nishiguchi, M. Kaito, S. Horiike, K. Fukuda, S. Inamoto, Y. Kitaura, Y. Nakamura, et al. Core Protein of Hepatitis C Virus Induces Cardiomyopathy Circ. Res., February 4, 2005; 96(2): 148 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Taimor, K.-D. Schluter, P. Best, S. Helmig, and H. M. Piper Transcription activator protein 1 mediates {alpha}- but not {beta}-adrenergic hypertrophic growth responses in adult cardiomyocytes Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2369 - H2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Morris, T. M. Pham, B. Kenney, K. E. Sheppard, and E. A. Woodcock UTP Transactivates Epidermal Growth Factor Receptors and Promotes Cardiomyocyte Hypertrophy Despite Inhibiting Transcription of the Hypertrophic Marker Gene, Atrial Natriuretic Peptide J. Biol. Chem., March 5, 2004; 279(10): 8740 - 8746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Omura, M. Yoshiyama, S. Kim, R. Matsumoto, Y. Nakamura, Y. Izumi, H. Ichijo, T. Sudo, K. Akioka, H. Iwao, et al. Involvement of Apoptosis Signal-Regulating Kinase-1 on Angiotensin II-Induced Monocyte Chemoattractant Protein-1 Expression Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 270 - 275. [Abstract] [Full Text]
|
|
|
|
|
|
W. Nadruz Jr., C. B. Kobarg, J. Kobarg, and K. G. Franchini c-Jun is regulated by combination of enhanced expression and phosphorylation in acute-overloaded rat heart Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H760 - H767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Morlon and P. Sassone-Corsi The LIM-only protein FHL2 is a serum-inducible transcriptional coactivator of AP-1 PNAS, April 1, 2003; 100(7): 3977 - 3982. [Abstract] [Full Text] [PDF]
|
|