Published Online
on August 18, 2008

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

This Article Full Text (PDF) Data Supplement All Versions of this Article: 118/10/1021    most recent CIRCULATIONAHA.108.777169v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Han, J.-K. Articles by Kim, H.-S. Search for Related Content PubMed PubMed Citation Articles by Han, J.-K. Articles by Kim, H.-S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Stem Cells Vascular Diseases Related Collections Angiogenesis Endothelium/vascular type/nitric oxide Related Article

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

Related Article:

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

This article has been cited by other articles:

				E. Ehrenborg and A. Krook Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor {delta} Pharmacol. Rev., September 1, 2009; 61(3): 373 - 393. [Abstract] [Full Text] [PDF]