Peroxisome proliferator-activated receptor-δ agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway

Hyo Soo Kim, Jung Kyu Han, Hyun Sook Lee, Han Mo Yang, Jin Hur, Soo In Jun, Ju Young Kim, Chung Hyun Cho, Gou Young Koh, Jeffrey Maurice Peters, Kyung Woo Park, Hyun Jai Cho, Hae Young Lee, Hyun Jae Kang, Byung Hee Oh, Young Bae Park

Research output: Contribution to journalArticle

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

Original languageEnglish (US)
Pages (from-to)1021-1033
Number of pages13
JournalCirculation
Volume118
Issue number10
DOIs
StatePublished - Sep 2 2008

Fingerprint

Phosphatidylinositol 3-Kinase
Peroxisome Proliferator-Activated Receptors
Hindlimb
4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid
Endothelial Progenitor Cells
Corneal Neovascularization
Transendothelial and Transepithelial Migration
Limb Salvage
Therapeutics
Cytoplasmic and Nuclear Receptors
Hematopoietic Stem Cells
Vascular Diseases
Knockout Mice
Bone Marrow Cells
Blood Vessels
Cardiovascular Diseases
Extremities
Transplantation
Bone Marrow
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kim, Hyo Soo ; 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 Maurice ; Park, Kyung Woo ; Cho, Hyun Jai ; Lee, Hae Young ; Kang, Hyun Jae ; Oh, Byung Hee ; Park, Young Bae. / Peroxisome proliferator-activated receptor-δ agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway. In: Circulation. 2008 ; Vol. 118, No. 10. pp. 1021-1033.
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title = "Peroxisome proliferator-activated receptor-δ agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway",
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)-δ 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-δ 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-δ activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-δ activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-δ activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-δ agonist-treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-δ-knockout mice, however, treatment with PPAR-δ agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-δ 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-δ agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.",
author = "Kim, {Hyo Soo} and Han, {Jung Kyu} and Lee, {Hyun Sook} and Yang, {Han Mo} and Jin Hur and Jun, {Soo In} and Kim, {Ju Young} and Cho, {Chung Hyun} and Koh, {Gou Young} and Peters, {Jeffrey Maurice} and Park, {Kyung Woo} and Cho, {Hyun Jai} and Lee, {Hae Young} and Kang, {Hyun Jae} and Oh, {Byung Hee} and Park, {Young Bae}",
year = "2008",
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Peroxisome proliferator-activated receptor-δ agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway. / Kim, Hyo Soo; 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 Maurice; Park, Kyung Woo; Cho, Hyun Jai; Lee, Hae Young; Kang, Hyun Jae; Oh, Byung Hee; Park, Young Bae.

In: Circulation, Vol. 118, No. 10, 02.09.2008, p. 1021-1033.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Peroxisome proliferator-activated receptor-δ agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway

AU - Kim, Hyo Soo

AU - Han, Jung Kyu

AU - Lee, Hyun Sook

AU - Yang, Han Mo

AU - Hur, Jin

AU - Jun, Soo In

AU - Kim, Ju Young

AU - Cho, Chung Hyun

AU - Koh, Gou Young

AU - Peters, Jeffrey Maurice

AU - Park, Kyung Woo

AU - Cho, Hyun Jai

AU - Lee, Hae Young

AU - Kang, Hyun Jae

AU - Oh, Byung Hee

AU - Park, Young Bae

PY - 2008/9/2

Y1 - 2008/9/2

N2 - 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)-δ 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-δ 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-δ activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-δ activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-δ activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-δ agonist-treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-δ-knockout mice, however, treatment with PPAR-δ agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-δ 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-δ agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.

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

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DO - 10.1161/CIRCULATIONAHA.108.777169

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