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Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension

Gene Therapy volume 13, pages 348–355 (2006)Cite this article

Abstract

Cardiac activator protein-1 (AP-1), composed of c-Jun, is significantly activated by hypertension or angiotensin II (AngII). This study was undertaken to elucidate whether c-Jun could be the potential target for treatment of cardiac hypertrophy. We constructed recombinant adenovirus carrying dominant-negative mutant of c-Jun (Ad.DN-c-Jun). Using catheter-based technique of adenoviral gene transfer, we achieved global myocardial transduction of DN-c-Jun in rats, to specifically inhibit cardiac AP-1. (1) AngII (200 ng/kg/min) infusion in rats caused cardiac hypertrophy, increased cardiac p70S6 kinase activity by 1.3-fold (P<0.05) and enhanced the gene expression of cardiac hypertrophic markers. Ad.DN-c-Jun, which was transferred to the heart 2 days before AngII infusion, prevented cardiac hypertrophy (P<0.01), decreased p70S6 kinase phosphorylation (P<0.05), and suppressed cardiac gene expression of brain natriuretic peptide, collagen I, III, and IV, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) (P<0.01). (2) In genetically hypertensive rats with cardiac hypertrophy, cardiac gene transfer of Ad.DN-c-Jun, without affecting hypertension, regressed cardiac hypertrophy (P<0.05), and suppressed p70S6 kinase phosphorylation by 20% (P<0.05) and suppressed the enhanced expression of collagen I, III, and IV, MCP-1 and PAI-1. These results provided the first evidence that in vivo blockade of cardiac c-Jun inhibits pathologic cardiac hypertrophy.

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References

  1. Leppa S, Bohmann D . Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 1999; 18: 6158–6162.

    Article  CAS  Google Scholar 

  2. Yasumoto H, Kim S, Zhan Y, Miyazaki H, Hoshiga M, Kaneda Y et al. Dominant negative c-jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in rats. Gene Therapy 2001; 8: 1682–1689.

    Article  CAS  Google Scholar 

  3. Zhan Y, Kim S, Yasumoto H, Namba M, Miyazaki H, Iwao H . Effects of dominant-negative c-Jun on platelet-derived growth factor-induced vascular smooth muscle cell proliferation. Arterioscler Thromb Vasc Biol 2002; 22: 82–88.

    Article  CAS  Google Scholar 

  4. Yano M, Kim S, Izumi Y, Yamanaka S, Iwao H . Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated kinase in angiotensin II-mediated hypertension. Circ Res 1998; 83: 752–760.

    Article  CAS  Google Scholar 

  5. Izumi Y, Kim S, Murakami T, Yamanaka S, Iwao H . Cardiac mitogen-activated protein kinase activities are chronically increased in stroke-prone hypertensive rats. Hypertension 1998; 31: 50–56.

    Article  CAS  Google Scholar 

  6. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H . Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension 1995; 25: 1252–1259.

    Article  CAS  Google Scholar 

  7. Brown PH, Chen TK, Birrer MJ . Mechanism of action of a dominant-negative mutant of c-Jun. Oncogene 1994; 9: 791–799.

    CAS  PubMed  Google Scholar 

  8. Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K et al. Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome. Proc Natl Acad Sci USA 1996; 93: 1320–1324.

    Article  CAS  Google Scholar 

  9. Xu ZL, Mizuguchi H, Mayumi T, Hayakawa T . Regulated gene expression from adenovirus vectors: a systematic comparison of various inducible systems. Gene 2003; 309: 145–151.

    Article  CAS  Google Scholar 

  10. Hajjar RJ, Schmidt U, Matsui T, Guerrero JL, Lee KH, Gwathmey JK et al. Modulation of ventricular function through gene transfer in vivo. Proc Natl Acad Sci USA 1998; 95: 5251–5256.

    Article  CAS  Google Scholar 

  11. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K et al. Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995; 273: 509–515.

    CAS  PubMed  Google Scholar 

  12. Suto R, Tominaga K, Mizuguchi H, Sasaki E, Higuchi K, Kim S et al. Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer. Gene Therapy 2004; 11: 187–193.

    Article  CAS  Google Scholar 

  13. Omura T, Yoshiyama M, Yoshida K, Nakamura Y, Kim S, Iwao H et al. Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine. Hypertension 2002; 39: 81–86.

    Article  CAS  Google Scholar 

  14. Kim S, Iwao H . Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52: 11–34.

    CAS  PubMed  Google Scholar 

  15. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H . Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. Br J Pharmacol 1996; 118: 549–556.

    Article  CAS  Google Scholar 

  16. Schmelzle T, Hall MN . TOR, a central controller of cell growth. Cell 2000; 103: 253–262.

    Article  CAS  Google Scholar 

  17. Boluyt MO, Zheng JS, Younes A, Long X, O'Neill L, Silverman H et al. Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes. Evidence for involvement of p70 S6 kinase. Circ Res 1997; 81: 176–186.

    Article  CAS  Google Scholar 

  18. Sadoshima J, Izumo S . Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ Res 1995; 77: 1040–1052.

    Article  CAS  Google Scholar 

  19. Shioi T, McMullen JR, Tarnavski O, Converso K, Sherwood MC, Manning WJ et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 2003; 107: 1664–1670.

    Article  CAS  Google Scholar 

  20. Kim S, Zhan Y, Izumi Y, Iwao H . Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. Hypertension 2000; 35: 769–774.

    Article  CAS  Google Scholar 

  21. Izumi Y, Kim S, Zhan Y, Namba M, Yasumoto H, Iwao H . Important role of angiotensin II-mediated c-Jun NH(2)-terminal kinase activation in cardiac hypertrophy in hypertensive rats. Hypertension 2000; 36: 511–516.

    Article  CAS  Google Scholar 

  22. Nadal-Ginard B, Mahdavi V . Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J Clin Invest 1989; 84: 1693–1700.

    Article  CAS  Google Scholar 

  23. Parker TG, Schneider MD . Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol 1991; 53: 179–200.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture (14370036 and 14570083), and Hoh-ansha Foundation.

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Authors and Affiliations

  1. Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

    S Kim-Mitsuyama

  2. Department of Pharmacology, Osaka City University Medical School, Abeno-ku, Osaka, Japan

    Y Izumi, Y Izumiya, M Namba, K Yoshida, R Wake & H Iwao

  3. Department of Internal Medicine and Cardiology, Osaka City University Medical School, Abeno-ku, Osaka, Japan

    M Yoshiyama

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  1. S Kim-Mitsuyama
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  2. Y Izumi
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Correspondence to S Kim-Mitsuyama.

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Kim-Mitsuyama, S., Izumi, Y., Izumiya, Y. et al. Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension. Gene Ther 13, 348–355 (2006). https://doi.org/10.1038/sj.gt.3302670

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  • DOI: https://doi.org/10.1038/sj.gt.3302670

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