Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 457K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, C. Articles by Tigyi, G. Search for Related Content PubMed PubMed Citation Articles by Zhang, C. Articles by Tigyi, G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Carotid Artery Disease Social Bookmarking                      What's this?

Lysophosphatidic Acid Induces Neointima Formation Through PPAR Activation

¹ The University of Tennessee Health Science Center, Vascular Biology Center or Excellence, ² Genomics and Bioinformatics Center of Excellence, ³ Department of Physiology and ⁴ Department of Pathology, Memphis, TN 38163
⁵ The University of Utah, Program in Human Molecular Biology and Genetics, and ⁶ Department of Medicinal Chemistry and Center for Cell Signaling, Salt Lake City, UT 84108
⁷ Queens College of City University of New York, Department of Chemistry and Biochemistry, Flushing, NY 11367

Address correspondence to Gabor Tigyi, University of Tennessee Health Science Center, Dept. of Physiology, 894 Union Ave., Memphis, TN 38163. Phone: (901) 448-4793; Fax: (901) 448-7126; email: gtigyi{at}physio1.utmem.edu

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

Key Words: neointima • LPA • PPAR • atherogenesis • lipid mediator

C. Zhang and D.L. Baker contributed equally to this work.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Sato, H., Kato, R., Isogai, Y., Saka, G.-i., Ohtsuki, M., Taketomi, Y., Yamamoto, K., Tsutsumi, K., Yamada, J., Masuda, S., Ishikawa, Y., Ishii, T., Kobayashi, T., Ikeda, K., Taguchi, R., Hatakeyama, S., Hara, S., Kudo, I., Itabe, H., Murakami, M. (2008). Analyses of Group III Secreted Phospholipase A2 Transgenic Mice Reveal Potential Participation of This Enzyme in Plasma Lipoprotein Modification, Macrophage Foam Cell Formation, and Atherosclerosis. J. Biol. Chem. 283: 33483-33497 [Abstract] [Full Text]  
• Yu, S., Murph, M. M., Lu, Y., Liu, S., Hall, H. S., Liu, J., Stephens, C., Fang, X., Mills, G. B. (2008). Lysophosphatidic Acid Receptors Determine Tumorigenicity and Aggressiveness of Ovarian Cancer Cells. JNCI J Natl Cancer Inst 100: 1630-1642 [Abstract] [Full Text]  
• Gustin, C., Van Steenbrugge, M., Raes, M. (2008). LPA modulates monocyte migration directly and via LPA-stimulated endothelial cells. Am. J. Physiol. Cell Physiol. 295: C905-C914 [Abstract] [Full Text]  
• Panchatcharam, M., Miriyala, S., Yang, F., Rojas, M., End, C., Vallant, C., Dong, A., Lynch, K., Chun, J., Morris, A. J., Smyth, S. S. (2008). Lysophosphatidic Acid Receptors 1 and 2 Play Roles in Regulation of Vascular Injury Responses but Not Blood Pressure. Circ. Res. 103: 662-670 [Abstract] [Full Text]  
• Walkey, C. J., Spiegelman, B. M. (2008). A Functional Peroxisome Proliferator-activated Receptor-{gamma} Ligand-binding Domain Is Not Required for Adipogenesis. J. Biol. Chem. 283: 24290-24294 [Abstract] [Full Text]  
• Ishdorj, G., Graham, B. A., Hu, X., Chen, J., Johnston, J. B., Fang, X., Gibson, S. B. (2008). Lysophosphatidic Acid Protects Cancer Cells from Histone Deacetylase (HDAC) Inhibitor-induced Apoptosis through Activation of HDAC. J. Biol. Chem. 283: 16818-16829 [Abstract] [Full Text]  
• Valentine, W. J., Fells, J. I., Perygin, D. H., Mujahid, S., Yokoyama, K., Fujiwara, Y., Tsukahara, R., Van Brocklyn, J. R., Parrill, A. L., Tigyi, G. (2008). Subtype-specific Residues Involved in Ligand Activation of the Endothelial Differentiation Gene Family Lysophosphatidic Acid Receptors. J. Biol. Chem. 283: 12175-12187 [Abstract] [Full Text]  
• Murph, M. M., Hurst-Kennedy, J., Newton, V., Brindley, D. N., Radhakrishna, H. (2007). Lysophosphatidic Acid Decreases the Nuclear Localization and Cellular Abundance of the p53 Tumor Suppressor in A549 Lung Carcinoma Cells. Mol Cancer Res 5: 1201-1211 [Abstract] [Full Text]  
• Ji, R., Cheng, Y., Yue, J., Yang, J., Liu, X., Chen, H., Dean, D. B., Zhang, C. (2007). MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation. Circ. Res. 100: 1579-1588 [Abstract] [Full Text]  
• Damirin, A., Tomura, H., Komachi, M., Liu, J.-P., Mogi, C., Tobo, M., Wang, J.-Q., Kimura, T., Kuwabara, A., Yamazaki, Y., Ohta, H., Im, D.-S., Sato, K., Okajima, F. (2007). Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 292: H2513-H2522 [Abstract] [Full Text]  
• Goetzl, E. J. (2007). Diverse pathways for nuclear signaling by G protein-coupled receptors and their ligands. FASEB J. 21: 638-642 [Abstract] [Full Text]  
• Pilquil, C., Dewald, J., Cherney, A., Gorshkova, I., Tigyi, G., English, D., Natarajan, V., Brindley, D. N. (2006). Lipid Phosphate Phosphatase-1 Regulates Lysophosphatidate-induced Fibroblast Migration by Controlling Phospholipase D2-dependent Phosphatidate Generation. J. Biol. Chem. 281: 38418-38429 [Abstract] [Full Text]  
• Yang, J., Cheng, Y., Ji, R., Zhang, C. (2006). Novel model of inflammatory neointima formation reveals a potential role of myeloperoxidase in neointimal hyperplasia. Am. J. Physiol. Heart Circ. Physiol. 291: H3087-H3093 [Abstract] [Full Text]  
• Murph, M., Tanaka, T., Liu, S., Mills, G. B. (2006). Of Spiders and Crabs: The Emergence of Lysophospholipids and Their Metabolic Pathways as Targets for Therapy in Cancer.. Clin. Cancer Res. 12: 6598-6602 [Abstract] [Full Text]  
• Han, M., Wen, J.-K., Zheng, B., Cheng, Y., Zhang, C. (2006). Serum deprivation results in redifferentiation of human umbilical vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 291: C50-C58 [Abstract] [Full Text]  
• Tsukahara, T., Tsukahara, R., Yasuda, S., Makarova, N., Valentine, W. J., Allison, P., Yuan, H., Baker, D. L., Li, Z., Bittman, R., Parrill, A., Tigyi, G. (2006). Different Residues Mediate Recognition of 1-O-Oleyllysophosphatidic Acid and Rosiglitazone in the Ligand Binding Domain of Peroxisome Proliferator-activated Receptor {gamma}. J. Biol. Chem. 281: 3398-3407 [Abstract] [Full Text]  
• Lin, D. A., Boyce, J. A. (2005). IL-4 Regulates MEK Expression Required for Lysophosphatidic Acid-Mediated Chemokine Generation by Human Mast Cells. J. Immunol. 175: 5430-5438 [Abstract] [Full Text]  
• Fujiwara, Y., Sardar, V., Tokumura, A., Baker, D., Murakami-Murofushi, K., Parrill, A., Tigyi, G. (2005). Identification of Residues Responsible for Ligand Recognition and Regioisomeric Selectivity of Lysophosphatidic Acid Receptors Expressed in Mammalian Cells. J. Biol. Chem. 280: 35038-35050 [Abstract] [Full Text]  
• Bektas, M., Payne, S. G., Liu, H., Goparaju, S., Milstien, S., Spiegel, S. (2005). A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells. JCB 169: 801-811 [Abstract] [Full Text]  
• Luna-Medina, R., Cortes-Canteli, M., Alonso, M., Santos, A., Martinez, A., Perez-Castillo, A. (2005). Regulation of Inflammatory Response in Neural Cells in Vitro by Thiadiazolidinones Derivatives through Peroxisome Proliferator-activated Receptor {gamma} Activation. J. Biol. Chem. 280: 21453-21462 [Abstract] [Full Text]  
• Ben-Shlomo, I., Hsueh, A. J. W. (2005). Three's Company: Two or More Unrelated Receptors Pair with the Same Ligand. Mol. Endocrinol. 19: 1097-1109 [Abstract] [Full Text]  
• Simon, M. F., Daviaud, D., Pradere, J. P., Gres, S., Guigne, C., Wabitsch, M., Chun, J., Valet, P., Saulnier-Blache, J. S. (2005). Lysophosphatidic Acid Inhibits Adipocyte Differentiation via Lysophosphatidic Acid 1 Receptor-dependent Down-regulation of Peroxisome Proliferator-activated Receptor {gamma}2. J. Biol. Chem. 280: 14656-14662 [Abstract] [Full Text]  
• Schopfer, F. J., Lin, Y., Baker, P. R. S., Cui, T., Garcia-Barrio, M., Zhang, J., Chen, K., Chen, Y. E., Freeman, B. A. (2005). Nitrolinoleic acid: An endogenous peroxisome proliferator-activated receptor {gamma} ligand. Proc. Natl. Acad. Sci. USA 102: 2340-2345 [Abstract] [Full Text]  
• Chemin, J., Patel, A., Duprat, F., Zanzouri, M., Lazdunski, M., Honore, E. (2005). Lysophosphatidic Acid-operated K+ Channels. J. Biol. Chem. 280: 4415-4421 [Abstract] [Full Text]  
• Llodra, J., Angeli, V., Liu, J., Trogan, E., Fisher, E. A., Randolph, G. J. (2004). From the Cover: Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc. Natl. Acad. Sci. USA 101: 11779-11784 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS