Effects of a PPAR-gamma agonist, on growth factor and insulin stimulated endothelial cells.
OBJECTIVE
PPAR-gamma agonists such as thiazolidinediones, used in patients with insulin resistance have been shown to reduce neointimal hyperplasia in the short term. However recent studies suggest increased cardiovascular risk for some thiazolidinediones. Longer-term animal studies show inhibition of endothelial regrowth post endothelial injury which may account for some of the increased risk. We studied the effect of pioglitazone on VEGF, FGF and insulin stimulated endothelial cells to determine if this was a mechanism of inhibition of endothelial regrowth.


RESULTS
FGF/VEGF stimulated human umbilical vein endothelial cell (HUVEC) proliferation and apoptosis was measured, in vitro, in the presence and absence of hyperinsulinemia, with and without treatment with the PPAR-gamma agonist pioglitazone. Activation of ERK 1/2 and p38MAPK was measured under the same conditions. There was 40% decrease in proliferation with pioglitazone in VEGF stimulated cells, which was reversed by insulin. ERK 1/2 activation was decreased by pioglitazone in VEGF stimulated cells and was partially reversed by insulin. p38MAPK activation was increased by pioglitazone and was unaffected by insulin or VEGF. Pioglitazone also increased endothelial cell apoptosis.


CONCLUSIONS
PPAR-gamma agonists may have detrimental cardiovascular effects post angioplasty especially in patients with insulin resistance. We have shown that one of the mechanisms may be inhibition of endothelial regrowth and re-endothelialization by inhibition of VEGF/FGF stimulation of the ERK 1/2 pathways in endothelial cells.
Desouza
Cyrus V
CV
Omaha Veterans Affairs Medical Center, United States; University of Nebraska Medical Center, United States. cdesouza@unmc.edu
Gerety
Moira
M
Hamel
Frederick G
FG
D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D042442:Vascular Endothelial Growth Factors; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077205:Pioglitazone