Lysophosphatidic acid induces neointima formation through PPARgamma activation.
Neointimal lesions are characterized by accumulation of cells within the arterial wall and are a prelude to atherosclerotic disease. Here we report that a brief exposure to either alkyl ether analogs of the growth factor-like phospholipid lysophosphatidic acid (LPA), products generated during the oxidative modification of low density lipoprotein, or to unsaturated acyl forms of LPA induce progressive formation of neointima in vivo in a rat carotid artery model. This effect is completely inhibited by the peroxisome proliferator-activated receptor (PPAR)gamma antagonist GW9662 and mimicked by PPARgamma agonists Rosiglitazone and 1-O-hexadecyl-2-azeleoyl-phosphatidylcholine. In contrast, stearoyl-oxovaleryl phosphatidylcholine, a PPARalpha agonist and polypeptide epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor failed to elicit neointima. The structure-activity relationship for neointima induction by LPA analogs in vivo is identical to that of PPARgamma activation in vitro and disparate from that of LPA G protein-coupled receptor activation. Neointima-inducing LPA analogs up-regulated the CD36 scavenger receptor in vitro and in vivo and elicited dedifferentiation of cultured vascular smooth muscle cells that was prevented by GW9662. These results suggest that selected LPA analogs are important novel endogenous PPARgamma ligands capable of mediating vascular remodeling and that activation of the nuclear transcription factor PPARgamma is both necessary and sufficient for neointima formation by components of oxidized low density lipoprotein.
University of Tennessee Health Science Center, Vascular Biology Center of Excellence, Memphis 38163, USA.
Chunxiang
C
Zhang
Daniel L
DL
Baker
Satoshi
S
Yasuda
Natalia
N
Makarova
Louisa
L
Balazs
Leonard R
LR
Johnson
Gopal K
GK
Marathe
Thomas M
TM
McIntyre
Yong
Y
Xu
Glenn D
GD
Prestwich
Hoe-Sup
HS
Byun
Robert
R
Bittman
Gabor
G
Tigyi
D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000139:chemically induced*; D002478:Cells, Cultured; D017931:DNA Primers; D004195:Disease Models, Animal; D006133:Growth Substances / Q000378:metabolism; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D008246:Lysophospholipids / Q000633:toxicity*; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000633:toxicity; D013997:Time Factors; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018955:CD36 Antigens; D002148:Calmodulin-Binding Proteins; D017931:DNA Primers; D006133:Growth Substances; D008024:Ligands; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone