Sonic hedgehog myocardial gene therapy: Tissue repair through transient reconstitution of embryonic signaling

Kengo F. Kusano, Roberto Pola, Toshinori Murayama, Cynthia Curry, Atsuhiko Kawamoto, Atsushi Iwakura, Satoshi Shintani, Masaaki Ii, Jun Asai, Tengiz Tkebuchava, Tina Thorne, Hideya Takenaka, Ryuichi Aikawa, David Goukassian, Patrick Von Samson, Hiromichi Hamada, Young Sup Yoon, Marcy Silver, Elizabeth Eaton, Hong MaLindsay Heyd, Marianne Kearney, William Munger, Jeffery A. Porter, Raj Kishore, Douglas W. Losordo

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Abstract

Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.

Original languageEnglish
Pages (from-to)1197-1204
Number of pages8
JournalNature Medicine
Volume11
Issue number11
DOIs
Publication statusPublished - 2005 Nov 1

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kusano, K. F., Pola, R., Murayama, T., Curry, C., Kawamoto, A., Iwakura, A., Shintani, S., Ii, M., Asai, J., Tkebuchava, T., Thorne, T., Takenaka, H., Aikawa, R., Goukassian, D., Von Samson, P., Hamada, H., Yoon, Y. S., Silver, M., Eaton, E., ... Losordo, D. W. (2005). Sonic hedgehog myocardial gene therapy: Tissue repair through transient reconstitution of embryonic signaling. Nature Medicine, 11(11), 1197-1204. https://doi.org/10.1038/nm1313