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 Ma; Lindsay Heyd; Marianne Kearney; William Munger; Jeffery A. Porter; Raj Kishore; Douglas W. Losordo

doi:10.1038/nm1313

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

BioMedical Science Institute

Research output: Contribution to journal › Article › peer-review

273 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 language	English
Pages (from-to)	1197-1204
Number of pages	8
Journal	Nature Medicine
Volume	11
Issue number	11
DOIs	https://doi.org/10.1038/nm1313
Publication status	Published - 2005 Nov

Bibliographical note

Funding Information:
The authors gratefully acknowledge the secretarial assistance of M. Neely and D. Costello in the preparation of this manuscript. This work was supported by US National Institutes of Health grants HL 63414, HL 80137, HL 53354, HL P01 66957 and HL 57516 (to D.W.L.) and American Heart Association grant 0325774T (to K.F.K.).

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm1313

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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

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title = "Sonic hedgehog myocardial gene therapy: Tissue repair through transient reconstitution of embryonic signaling",

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.",

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

note = "Funding Information: The authors gratefully acknowledge the secretarial assistance of M. Neely and D. Costello in the preparation of this manuscript. This work was supported by US National Institutes of Health grants HL 63414, HL 80137, HL 53354, HL P01 66957 and HL 57516 (to D.W.L.) and American Heart Association grant 0325774T (to K.F.K.).",

year = "2005",

month = nov,

doi = "10.1038/nm1313",

language = "English",

volume = "11",

pages = "1197--1204",

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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

TY - JOUR

T1 - Sonic hedgehog myocardial gene therapy

T2 - Tissue repair through transient reconstitution of embryonic signaling

AU - Kusano, Kengo F.

AU - Pola, Roberto

AU - Murayama, Toshinori

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.

N1 - Funding Information: The authors gratefully acknowledge the secretarial assistance of M. Neely and D. Costello in the preparation of this manuscript. This work was supported by US National Institutes of Health grants HL 63414, HL 80137, HL 53354, HL P01 66957 and HL 57516 (to D.W.L.) and American Heart Association grant 0325774T (to K.F.K.).

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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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ER -

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

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