Publications
Detailed Information
Peroxisome proliferator-activated receptor-delta agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway
Cited 79 time in
Web of Science
Cited 77 time in Scopus
- Authors
- Issue Date
- 2008-08-20
- Publisher
- American Heart Association
- Citation
- Circulation. 2008;118(10):1021-1033
- Keywords
- 1-Phosphatidylinositol 3-Kinase/*metabolism ; Animals ; Blood Flow Velocity/drug effects ; Bone Marrow/metabolism ; Cells, Cultured ; Corneal Neovascularization/metabolism/pathology ; Disease Models, Animal ; Endothelial Cells/*metabolism/pathology ; Female ; Hematopoietic Stem Cells/*metabolism/pathology ; Hindlimb/metabolism/pathology ; Humans ; Ischemia/*metabolism/pathology/therapy ; Male ; Mice ; Mice, Knockout ; Neovascularization, Physiologic/*drug effects ; PPAR delta/*agonists/metabolism ; Proto-Oncogene Proteins c-akt ; Stem Cell Transplantation ; Thiazoles/*pharmacology ; Vascular Diseases/*metabolism/pathology/therapy
- Abstract
- BACKGROUND: Despite the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, their insufficient numbers limit clinical applications. Peroxisome proliferator-activated receptor (PPAR)-delta belongs to the nuclear hormone receptor superfamily, and its functions in various tissues and cells are almost unexplored, especially with respect to vascular biology. METHODS AND RESULTS: PPAR-delta activation in EPCs phosphorylated Akt, and this phosphorylation was mediated not only by genomic but also by nongenomic pathways through interaction with the regulatory subunit of phosphatidylinositol 3-kinase. PPAR-delta activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-delta activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-delta activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-delta agonist-treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-delta-knockout mice, however, treatment with PPAR-delta agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-delta agonist increased hematopoietic stem cells in bone marrow and EPCs in peripheral blood, leading to improved vasculogenesis with incorporation of bone marrow-derived cells to new vessels in a corneal neovascularization model and limb salvage with better blood flow in an ischemic hindlimb model. CONCLUSIONS: The results of our study suggest that PPAR-delta agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.
- ISSN
- 1524-4539 (Electronic)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18711014
http://circ.ahajournals.org/cgi/reprint/118/10/1021.pdf
https://hdl.handle.net/10371/67930
- Files in This Item:
- Appears in Collections:
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.