Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis.
BACKGROUND
Plasma high-density lipoprotein (HDL) levels have an inverse correlation with incidence of ischemic heart disease as well as other atherosclerosis-related ischemic conditions. However, the molecular mechanism by which HDL prevents ischemic disease is not fully understood. Here, we investigated the effect of HDL on differentiation of endothelial progenitor cells and angiogenesis in murine ischemic hindlimb model.


RESULTS
Intravenous injection of reconstituted HDL (rHDL) significantly augmented blood flow recovery and increased capillary density in the ischemic leg. rHDL increased the number of bone marrow-derived cells incorporated into the newly formed capillaries in ischemic muscle. rHDL induced phosphorylation of Akt in human peripheral mononuclear cells. rHDL (50 to 100 microg apolipoprotein A-I/mL) promoted differentiation of peripheral mononuclear cells to endothelial progenitor cells in a dose-dependent manner. The effect of rHDL on endothelial progenitor cells differentiation was abrogated by coadministration of LY294002, an inhibitor of phosphatidylinositol 3-kinase. rHDL failed to promote angiogenesis in endothelial NO-deficient mice.


CONCLUSIONS
rHDL directly stimulates endothelial progenitor cell differentiation via phosphatidylinositol 3-kinase/Akt pathway and enhances ischemia-induced angiogenesis. rHDL may be useful in the treatment of patients with ischemic cardiovascular diseases.
Sumi
Makoto
M
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Sata
Masataka
M
Miura
Shin-ichiro
S
Rye
Kerry-Anne
KA
Toya
Naoki
N
Kanaoka
Yuji
Y
Yanaga
Katsuhiko
K
Ohki
Takao
T
Saku
Keijiro
K
Nagai
Ryozo
R
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002678:Chimera; D003097:Collateral Circulation / Q000187:drug effects; D042783:Endothelial Cells / Q000473:pathology*; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000503:physiopathology*; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction; D013234:Stem Cells / Q000473:pathology*
D008075:Lipoproteins, HDL; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt