| 한정규¹ ², 이현숙¹ , 양한모¹ , 허진¹ , 전수인¹ , 이해영¹ ² , 강현재¹ ² , 손대원¹ ² , 오병희¹ ² , 박영배¹ ² , 최윤식¹ ² , 김효수¹ ² |
Background: In spite of the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, the insufficient numbers and angiogenic capacity set limit to clinical application. Peroxisome proliferator-activated receptor (PPAR)-δ belongs to the nuclear receptor superfamily and is suggested to have beneficial effects in obesity and dyslipidemia. However, in contrast to PPAR-γ, its roles in various tissues and cells are nearly unexplored, especially in vascular system including EPCs. Thus, we evaluated the role of PPAR-δ on EPC survival and function.
Methods and Results: PPAR-δ activation by GW501516, a potent and highly selective PPAR-δ agonist, resulted in increased EPC survival and proliferation evaluated by trypan blue exclusion assay and cell cycle FACS analysis, respectively. When evaluated with apoptosis FACS, GW501516 also protected EPCs from hypoxia induced apoptosis dose dependently.. Moreover, GW501516 enhanced EPC function in terms of transendothelial migration, secretion of vasculogenic cytokines such as IL-8 and VEGF, and capillary tube formation when co-cultured with ECs on Matrigel. These actions of PPAR-δ agonist in EPCs were mediated via the PI3K/Akt signal pathway. PPAR-δ agonist activatedAkt through not only genomic but also nongenomic pathway. The latter rapid and nontranscriptionally mediated phosphorylation occurred by interaction between PPAR-δ and p85α, the regulatory subunit of PI3K. LY294002, a PI3K inhibitor, reversed above mentioned various effects of PPAR-δ activation in EPCs.. Next, in order to confirm the vasculogenic potency of PPAR-δ agonist, in vivo studies were performed. GW501516 priming potentiated the effect of EPCs on vessel formation, resulting increased limb salvage in mouse hindlimb ischemia model.In corneal injury model of BMT mouse, GW501516 therapy was found to proliferate hematopoietic stem cells in BM, subsequently increase the numbers of EPCs in peripheral blood, and ultimately promote cornea neovascularization.to .
Conclusions: Augmentation of mobilization and vasculogenic capacity of EPCs by PPAR-δ agonist suggestit as a new and unique therapeutic choice in ischemic vascular diseases.
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