Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling.
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.
Kusano
Kengo F
KF
Division of Cardiovascular Research, St. Elizabeth Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Pola
Roberto
R
Murayama
Toshinori
T
Curry
Cynthia
C
Kawamoto
Atsuhiko
A
Iwakura
Atsushi
A
Shintani
Satoshi
S
Ii
Masaaki
M
Asai
Jun
J
Tkebuchava
Tengiz
T
Thorne
Tina
T
Takenaka
Hideya
H
Aikawa
Ryuichi
R
Goukassian
David
D
von Samson
Patrick
P
Hamada
Hiromichi
H
Yoon
Young-sup
YS
Silver
Marcy
M
Eaton
Elizabeth
E
Ma
Hong
H
Heyd
Lindsay
L
Kearney
Marianne
M
Munger
William
W
Porter
Jeffery A
JA
Kishore
Raj
R
Losordo
Douglas W
DW
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
D053823:Hedgehog Proteins; D012333:RNA, Messenger; C509239:SHH protein, human; D015534:Trans-Activators