Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling.
OBJECTIVE
The peroxisome proliferator activated receptor-gamma (PPARgamma) protein is a nuclear transcriptional activator with importance in diabetes management as the molecular target for the thiazolidinedione (TZD) family of drugs. Substantial evidence indicates that the TZD family of PPARgamma agonists may retard the development of atherosclerosis. However, recent clinical data have suggested that at least one TZD may increase the risk of myocardial infarction and death from cardiovascular disease. In this study, we used a genetic approach to disrupt PPARgamma signaling to probe the protein's role in smooth muscle cell (SMC) responses that are important for atherosclerosis.


RESULTS
SMC isolated from transgenic mice harboring the dominate-negative P465L mutation in PPARgamma (PPARgamma(L/+)) exhibited greater proliferation and migration then did wild-type cells. Upregulation of ETS-1, but not ERK activation, correlated with enhanced proliferative and migratory responses PPARgamma(L/+) SMCs. After arterial injury, PPARgamma(L/+) mice had a approximately 4.3-fold increase in the development of intimal hyperplasia.


CONCLUSIONS
These findings are consistent with a normal role for PPARgamma in inhibiting SMC migration and proliferation in the context of restenosis or atherosclerosis.
Meredith
Dane
D
Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Panchatcharam
Manikandan
M
Miriyala
Sumitra
S
Tsai
Yau-Sheng
YS
Morris
Andrew J
AJ
Maeda
Nobuyo
N
Stouffer
George A
GA
Smyth
Susan S
SS
D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D013997:Time Factors; D014945:Wound Healing
D047495:PPAR gamma; D050784:Proto-Oncogene Protein c-ets-1; D048049:Extracellular Signal-Regulated MAP Kinases