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

Nature Medicine volume 11, pages 1197–1204 (2005)Cite this article

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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Figure 1: Sonic hedgehog pathway is activated by myocardial ischemia.
Figure 2: Shh gene therapy reduces infarct size and preserves myocardial function after myocardial infarction.
Figure 3: Shh gene therapy restored myocardial function and perfusion in chronic ischemia.
Figure 4: Shh enhances contribution of bone marrow–derived EPCs to myocardial recovery.
Figure 5: Shh reduces cardiomyocyte apoptosis in vivo and in vitro.

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Acknowledgements

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.).

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Authors and Affiliations

  1. Division of Cardiovascular Research, St. Elizabeth Medical Center, Tufts University School of Medicine, Boston, 02135, Massachusetts, USA

    Kengo F Kusano, 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, Raj Kishore & Douglas W Losordo

  2. Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy

    Roberto Pola

  3. Curis, Inc., 8 Moulton Street, Cambridge, 02138, Massachusetts, USA

    William Munger & Jeffery A Porter

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Correspondence to Douglas W Losordo.

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Competing interests

William Munger and Jeffery A. Porter are employees of Curis, Inc., which could benefit financially from commercialization of therapy studied in this article.

Supplementary information

Supplementary Fig. 1

Shh receptor Ptc1 is expressed in nucleus and cytoplasm of cardiomyocytes. (PDF 83 kb)

Supplementary Fig. 2

Shh receptor Ptc1 is expressed in nucleus and cytoplasm of cardiomyocytes. (PDF 89 kb)

Supplementary Fig. 3

Shh upregulates expression of multiple factors in adult fibroblasts. (PDF 58 kb)

Supplementary Methods (PDF 125 kb)

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Kusano, K., Pola, R., Murayama, T. et al. Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling. Nat Med 11, 1197–1204 (2005). https://doi.org/10.1038/nm1313

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