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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 71 time in Web of Science Cited 70 time in Scopus
Authors
Han, Jung-Kyu; Lee, Hyun-Sook; Yang, Han-Mo; Hur, Jin; Jun, Soo-In; Kim, Ju-Young; Cho, Chung-Hyun; Koh, Gou-Young; Peters, Jeffrey M; Park, Kyung-Woo; Cho, Hyun-Jai; Lee, Hae-Young; Kang, Hyun-Jae; Oh, Byung-Hee; Park, Young-Bae; Kim, Hyo-Soo
Issue Date
2008-08-20
Publisher
American Heart Association
Citation
Circulation. 2008;118(10):1021-1033
Keywords
1-Phosphatidylinositol 3-Kinase/*metabolismAnimalsBlood Flow Velocity/drug effectsBone Marrow/metabolismCells, CulturedCorneal Neovascularization/metabolism/pathologyDisease Models, AnimalEndothelial Cells/*metabolism/pathologyFemaleHematopoietic Stem Cells/*metabolism/pathologyHindlimb/metabolism/pathologyHumansIschemia/*metabolism/pathology/therapyMaleMiceMice, KnockoutNeovascularization, Physiologic/*drug effectsPPAR delta/*agonists/metabolismProto-Oncogene Proteins c-aktStem Cell TransplantationThiazoles/*pharmacologyVascular 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

http://hdl.handle.net/10371/67930
DOI
https://doi.org/10.1161/CIRCULATIONAHA.108.777169
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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