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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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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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  3. Y Izumiya
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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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