Nature Medicine 11, 1197 - 1204 (2005)
Published online: 23 October 2005; | doi:10.1038/nm1313
Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signalingKengo F Kusano1, Roberto Pola2, Toshinori Murayama1, Cynthia Curry1, Atsuhiko Kawamoto1, Atsushi Iwakura1, Satoshi Shintani1, Masaaki Ii1, Jun Asai1, Tengiz Tkebuchava1, Tina Thorne1, Hideya Takenaka1, Ryuichi Aikawa1, David Goukassian1, Patrick von Samson1, Hiromichi Hamada1, Young-sup Yoon1, Marcy Silver1, Elizabeth Eaton1, Hong Ma1, Lindsay Heyd1, Marianne Kearney1, William Munger3, Jeffery A Porter3, Raj Kishore1
& Douglas W Losordo11
Division of Cardiovascular Research, St. Elizabeth Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA. 2
Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy. 3
Curis, Inc., 8 Moulton Street, Cambridge, Massachusetts 02138, USA.
Correspondence should be addressed to Douglas W Losordo douglas.losordo@tufts.edu 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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