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Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model

Gene Therapy volume 19, pages 836–843 (2012)Cite this article

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Abstract

We investigated the long-term effects of human hepatocyte growth factor (HGF) gene therapy in a rat myocardial infarct model. Treatment adenovirus coexpressing the HGF therapeutic gene and the human sodium/iodide symporter (NIS) reporter gene or control adenovirus expressing the NIS gene alone were injected directly into the infarct border zone immediately after permanent coronary ligation in rats (n=6 each). A uniform disease state was confirmed in the acute phase in terms of impaired left ventricular (LV) function by cine magnetic resonance imaging (MRI), large infarct extent by 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) and successful gene transfer and expression by 99mTcO4− SPECT. After a 10-week follow-up, repeated cine MRI demonstrated no significant difference in the LV ejection fraction between the time points or groups, but a significantly increased end-diastolic volume from the acute to the chronic phase without a significant difference between the groups. Capillary density was significantly higher in the treatment group, whereas arteriole density remained unchanged. Two-photon excitation fluorescence microscopy revealed extremely thin capillaries (2–5 μm), and their irregular networks increased in the infarct border zone of the treated myocardium. Our results indicated that single HGF gene therapy alone induced an immature and irregular microvasculature.

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Acknowledgements

We thank Professor Masanori Hatakeyama of University of Tokyo and Professor Hideaki Higashi of Hokkaido University for technical guidance in molecular biology, and Ms Sayaka Shibata and Mr Shigeyoshi Saito of National Institute of Radiological Sciences for assisting MRI experiments. We also thank SII NanoTechnology Inc. for providing us the small-animal SPECT/CT system. This study was supported in part by Grants-in-Aid for Scientific Research (B) (general; MI nos. 18390326 and 22390239) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government.

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Authors and Affiliations

  1. Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan

    Y-N Jin, M Inubushi, K Masamoto, K Odaka, I Aoki, A B Tsuji, M Sagara, M Koizumi & T Saga

  2. Center for Frontier Science and Engineering, University of Electro-Communications, Chofu, Japan

    K Masamoto

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  1. Y-N Jin
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Correspondence to M Inubushi.

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Jin, YN., Inubushi, M., Masamoto, K. et al. Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model. Gene Ther 19, 836–843 (2012). https://doi.org/10.1038/gt.2011.128

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