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Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy

Gene Therapy volume 13, pages 1206–1213 (2006)Cite this article

Abstract

Impairment of cardiac function in ischemic cardiomyopathy has been postulated to be due to the decrease in blood flow and increase in collagen synthesis. Therefore, an approach to alter them directly by means of a growth factor may open up a new therapeutic concept in ischemic cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with angiogenic and antifibrotic effects. Thus, we examined the feasibility of gene therapy using HGF plasmid DNA for ischemic cardiomyopathy. Human HGF plasmid DNA at a dose of 0.4 or 4 mg was injected into ischemic myocardium of pigs induced by ameroid constrictor with the NOGA system. At 1 month after injection, the ischemic area was significantly reduced in the HGF group, accompanied by a significant increase in capillary density and regional myocardial perfusion in the ischemic area (P<0.01). In contrast, a significant decrease in fibrotic area was observed in the HGF group, associated with a significant decrease in collagen I, III and TGF-β synthesis as compared to the control group (P<0.01). Consistently, cardiac function was significantly improved in the 4 mg HGF group as compared to the control group (P<0.05). Overall, the present in vivo experiments demonstrated that intramyocardial injection of human HGF plasmid DNA in ischemic cardiomyopathy resulted in a significant improvement in cardiac function through an increase in blood flow and decrease in fibrosis. These favorable outcomes suggest potential utility to treat patients with ischemic heart disease using HGF gene transfer. Currently, a phase I study using human HGF plasmid DNA is ongoing to test the validity of this concept.

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Acknowledgements

This work was partially supported by a Grant-in-Aid from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), the Organization for Pharmaceutical Safety and Research, a Grant-in-Aid from The Ministry of Public Health and Welfare, a Grant-in-Aid from Japan Promotion of Science, and through Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

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Authors and Affiliations

  1. Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    J Azuma, Y Taniyama, Y Takeya, K Iekushi, M Aoki, N Dosaka & R Morishita

  2. Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    K Matsumoto & T Nakamura

  3. Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    J Azuma, Y Taniyama, Y Takeya, K Iekushi, M Aoki, N Dosaka & T Ogihara

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  1. J Azuma
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Correspondence to R Morishita.

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Azuma, J., Taniyama, Y., Takeya, Y. et al. Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Ther 13, 1206–1213 (2006). https://doi.org/10.1038/sj.gt.3302740

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  • DOI: https://doi.org/10.1038/sj.gt.3302740

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