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.
authors.affiliation: Division of Cardiovascular Research, St. Elizabeth Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
authors.forename: Kengo F
authors.initials: KF
authors.lastname: Kusano
authors.forename: Roberto
authors.initials: R
authors.lastname: Pola
authors.forename: Toshinori
authors.initials: T
authors.lastname: Murayama
authors.forename: Cynthia
authors.initials: C
authors.lastname: Curry
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwakura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shintani
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Jun
authors.initials: J
authors.lastname: Asai
authors.forename: Tengiz
authors.initials: T
authors.lastname: Tkebuchava
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Hideya
authors.initials: H
authors.lastname: Takenaka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Aikawa
authors.forename: David
authors.initials: D
authors.lastname: Goukassian
authors.forename: Patrick
authors.initials: P
authors.lastname: von Samson
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hamada
authors.forename: Young-sup
authors.initials: YS
authors.lastname: Yoon
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eaton
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Lindsay
authors.initials: L
authors.lastname: Heyd
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: William
authors.initials: W
authors.lastname: Munger
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Porter
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000208:Acute Disease; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002908:Chronic Disease; D004195:Disease Models, Animal; D004452:Echocardiography; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015316:Genetic Therapy; D006321:Heart / Q000196:embryology*; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D017202:Myocardial Ischemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013552:Swine; D015534:Trans-Activators / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger; C509239:SHH protein, human; D015534:Trans-Activators