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.
Bibliographical noteFunding 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)