Lysophosphatidic Acid Induces Neointima Formation Through PPARγ Activation

Chunxiang Zhang, Daniel L. Baker, Satoshi Yasuda, Natalia Makarova, Louisa Balazs, Leonard R. Johnson, Gopal K. Marathe, Thomas M. McIntyre, Yong Xu, Glenn D. Prestwich, Hoe Sup Byun, Robert Bittman, Gabor Tigyi

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

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)γ antagonist GW9662 and mimicked by PPARγ agonists Rosiglitazone and 1-O-hexadecyl-2-azeleoyl-phosphatidylcholine. In contrast, stearoyl-oxovaleryl phosphatidylcholine, a PPARα 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 PPARγ 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 PPARγ ligands capable of mediating vascular remodeling and that activation of the nuclear transcription factor PPARγ is both necessary and sufficient for neointima formation by components of oxidized low density lipoprotein.

Original languageEnglish (US)
Pages (from-to)763-774
Number of pages12
JournalJournal of Experimental Medicine
Volume199
Issue number6
DOIs
StatePublished - Mar 15 2004

Fingerprint

Neointima
Peroxisome Proliferator-Activated Receptors
rosiglitazone
Phosphatidylcholines
Scavenger Receptors
Platelet-Derived Growth Factor
Structure-Activity Relationship
G-Protein-Coupled Receptors
Vascular Smooth Muscle
LDL Lipoproteins
Carotid Arteries
Epidermal Growth Factor
Ether
Vascular Endothelial Growth Factor A
Smooth Muscle Myocytes
lysophosphatidic acid
Phospholipids
Intercellular Signaling Peptides and Proteins
Transcription Factors
Ligands

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Lysophosphatidic Acid Induces Neointima Formation Through PPARγ Activation. / Zhang, Chunxiang; Baker, Daniel L.; Yasuda, Satoshi; Makarova, Natalia; Balazs, Louisa; Johnson, Leonard R.; Marathe, Gopal K.; McIntyre, Thomas M.; Xu, Yong; Prestwich, Glenn D.; Byun, Hoe Sup; Bittman, Robert; Tigyi, Gabor.

In: Journal of Experimental Medicine, Vol. 199, No. 6, 15.03.2004, p. 763-774.

Research output: Contribution to journalArticle

Zhang, C, Baker, DL, Yasuda, S, Makarova, N, Balazs, L, Johnson, LR, Marathe, GK, McIntyre, TM, Xu, Y, Prestwich, GD, Byun, HS, Bittman, R & Tigyi, G 2004, 'Lysophosphatidic Acid Induces Neointima Formation Through PPARγ Activation', Journal of Experimental Medicine, vol. 199, no. 6, pp. 763-774. https://doi.org/10.1084/jem.20031619
Zhang, Chunxiang ; Baker, Daniel L. ; Yasuda, Satoshi ; Makarova, Natalia ; Balazs, Louisa ; Johnson, Leonard R. ; Marathe, Gopal K. ; McIntyre, Thomas M. ; Xu, Yong ; Prestwich, Glenn D. ; Byun, Hoe Sup ; Bittman, Robert ; Tigyi, Gabor. / Lysophosphatidic Acid Induces Neointima Formation Through PPARγ Activation. In: Journal of Experimental Medicine. 2004 ; Vol. 199, No. 6. pp. 763-774.
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