Published Online
on August 18, 2008

A more recent version of this article appeared on September 2, 2008

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Submitted on March 3, 2008
Accepted on June 24, 2008

Peroxisome Proliferator–Activated Receptor- Agonist Enhances Vasculogenesis by Regulating Endothelial Progenitor Cells Through Genomic and Nongenomic Activations of the Phosphatidylinositol 3-Kinase/Akt Pathway

Jung-Kyu Han MD, Hyun-Sook Lee MS, Han-Mo Yang MD, Jin Hur PhD, Soo-In Jun BS, Ju-Young Kim MS, Chung-Hyun Cho PhD, Gou-Young Koh MD, Jeffrey M. Peters PhD, Kyung-Woo Park MD, Hyun-Jai Cho MD, Hae-Young Lee MD, Hyun-Jae Kang MD, Byung-Hee Oh MD, Young-Bae Park MD^*, and Hyo-Soo Kim MD^*

From the National Research Laboratory for Cardiovascular Stem Cell, College of Medicine, Seoul National University, Seoul, Korea (J.-K.H., H.-S.L., H.-M.Y., J.H., S.-I.J., J.-Y.K., K.-W.P., H.-J.C., H.-Y.L., H.-J.K., B.-H.O., Y.-B.P., H.-S.K.); Department of Physiology, College of Medicine, Chungnam National University, Daejeon, Korea (C.-H.C.); Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea (G.-Y.K.); Department of Veterinary and Biomedical Sciences and Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park (J.M.P.); and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea (K.-W.P., H.-J.C., H.-Y.L., H.-J.K.; B.-H.O., Y.-B.P., H.-S.K.).

^* To whom correspondence should be addressed. E-mail: parkyb{at}snu.ac.kr or hyosoo{at}snu.ac.kr.

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)- 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- 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- activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR- activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR- activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR- agonist–treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-–knockout mice, however, treatment with PPAR- agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR- 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- agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.

Key words: progenitor cells, endothelial • peroxisome proliferator–activated receptors • vasculogenesis

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Circulation 2008 118: 979-980. [Extract] [Full Text]

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