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

Research output: Contribution to journalArticle

233 Citations (Scopus)

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

Fingerprint

Gene transfer
Gene therapy
Hedgehogs
Genetic Therapy
Repair
Tissue
Myocardial Ischemia
Endothelial cells
Thromboplastin
Fibroblasts
Embryonic Development
Bone
Animals
Apoptosis
Genes
Recovery
DNA
Left Ventricular Function
Cardiac Myocytes
Fibrosis

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., ... 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
Kusano, Kengo F. ; Pola, Roberto ; Murayama, Toshinori ; Curry, Cynthia ; Kawamoto, Atsuhiko ; Iwakura, Atsushi ; Shintani, Satoshi ; Ii, Masaaki ; Asai, Jun ; Tkebuchava, Tengiz ; Thorne, Tina ; Takenaka, Hideya ; Aikawa, Ryuichi ; Goukassian, David ; Von Samson, Patrick ; Hamada, Hiromichi ; Yoon, Young Sup ; Silver, Marcy ; Eaton, Elizabeth ; Ma, Hong ; Heyd, Lindsay ; Kearney, Marianne ; Munger, William ; Porter, Jeffery A. ; Kishore, Raj ; Losordo, Douglas W. / Sonic hedgehog myocardial gene therapy : Tissue repair through transient reconstitution of embryonic signaling. In: Nature Medicine. 2005 ; Vol. 11, No. 11. pp. 1197-1204.
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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.",
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Kusano, KF, 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, YS, Silver, M, Eaton, E, Ma, H, Heyd, L, Kearney, M, Munger, W, Porter, JA, Kishore, R & Losordo, DW 2005, 'Sonic hedgehog myocardial gene therapy: Tissue repair through transient reconstitution of embryonic signaling', Nature Medicine, vol. 11, no. 11, pp. 1197-1204. https://doi.org/10.1038/nm1313

Sonic hedgehog myocardial gene therapy : Tissue repair through transient reconstitution of embryonic signaling. / Kusano, Kengo F.; Pola, Roberto; Murayama, Toshinori; Curry, Cynthia; Kawamoto, Atsuhiko; Iwakura, Atsushi; Shintani, Satoshi; Ii, Masaaki; Asai, Jun; Tkebuchava, Tengiz; Thorne, Tina; Takenaka, Hideya; Aikawa, Ryuichi; Goukassian, David; Von Samson, Patrick; Hamada, Hiromichi; Yoon, Young Sup; Silver, Marcy; Eaton, Elizabeth; Ma, Hong; Heyd, Lindsay; Kearney, Marianne; Munger, William; Porter, Jeffery A.; Kishore, Raj; Losordo, Douglas W.

In: Nature Medicine, Vol. 11, No. 11, 01.11.2005, p. 1197-1204.

Research output: Contribution to journalArticle

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AU - Kusano, Kengo F.

AU - Pola, Roberto

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AU - Curry, Cynthia

AU - Kawamoto, Atsuhiko

AU - Iwakura, Atsushi

AU - Shintani, Satoshi

AU - Ii, Masaaki

AU - Asai, Jun

AU - Tkebuchava, Tengiz

AU - Thorne, Tina

AU - Takenaka, Hideya

AU - Aikawa, Ryuichi

AU - Goukassian, David

AU - Von Samson, Patrick

AU - Hamada, Hiromichi

AU - Yoon, Young Sup

AU - Silver, Marcy

AU - Eaton, Elizabeth

AU - Ma, Hong

AU - Heyd, Lindsay

AU - Kearney, Marianne

AU - Munger, William

AU - Porter, Jeffery A.

AU - Kishore, Raj

AU - Losordo, Douglas W.

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