QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.096271v1 317/2/651    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zahradka, P. Articles by Taylor, C. G. Search for Related Content PubMed PubMed Citation Articles by Zahradka, P. Articles by Taylor, C. G.

CARDIOVASCULAR

Peroxisome Proliferator-Activated Receptor and Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada (P.Z., B.W., M.F., N.Y., K.M.); and Departments of Human Nutritional Sciences (M.F., N.Y., C.G.T.) and Physiology (P.Z.), University of Manitoba, Winnipeg, Manitoba, Canada

Peroxisome proliferator-activated receptors (PPARs) and are expressed in smooth muscle cells (SMCs). This study was designed to compare the effects of PPAR and PPAR on SMC proliferation and migration and to determine how they operate. Treatment of SMCs from porcine coronary artery revealed that mitogen-stimulated DNA synthesis was blocked by the PPAR ligand 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643) and 15-deoxy-^12,14 prostaglandin J₂ (15d-PGJ₂) (a putative PPAR agonist) but not by the PPAR agonist rosiglitazone or the PPAR/ ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy acetic acid (GW501516). Inhibition of DNA synthesis by clofibrate and 2-(4-(2-(1-cyclohexanebutyl-3-cyclohexylureido)ethyl)phenylthio)-2-methylproprionic acid (GW7647) confirmed that SMC proliferation is affected by PPAR. This conclusion was supported by the fact that WY14,643 also inhibited the proliferation of H4IIE hepatoma cells (expressing only PPAR) but not A10 SMCs (expressing only PPAR1). In contrast, the effective inhibition of all cell types with 15d-PGJ₂ indicated that this compound probably operates via a PPAR-independent mechanism. Interestingly, rosiglitazone did not inhibit DNA synthesis of either H4IIE or A10 cells, suggesting that the activation of PPAR does not influence cell proliferation. Phosphorylation of cyclin-dependent kinase 2 and expression of proliferating cell nuclear antigen were inhibited by WY14,643 but not by rosiglitazone or 15d-PGJ₂, indicating that PPAR prevents progression into S phase. Although rosiglitazone did not block SMC proliferation, it (like WY14,643) reduced neointimal hyperplasia in vitro. This observation can be rationalized by the fact that both WY14,643 and rosiglitazone inhibit SMC migration, probably through matrix metalloproteinase 9. Our study therefore shows that selective interference with mediators of cell cycle progression and cell migration via activation of PPARs may prevent growth-related vascular diseases such as restenosis and atherosclerosis.

Address correspondence to: Peter Zahradka, Institute of Cardiovascular Sciences, St. Boniface Research Centre, 351 Tache Avenue, Winnipeg, MB, Canada R2H 2A6. E-mail: peterz{at}sbrc.ca

This article has been cited by other articles:

				B. Chopra, J. Hinley, M. B. Oleksiewicz, and J. Southgate Trans-Species Comparison of PPAR and RXR Expression by Rat and Human Urothelial Tissues Toxicol Pathol, April 1, 2008; 36(3): 485 - 495. [Abstract] [Full Text] [PDF]

				D.-H. Nam, S. Ramachandran, D.-K. Song, K.-Y. Kwon, D.-S. Jeon, S.-J. Shin, S.-H. Kwon, S.-D. Cha, I. Bae, and C.-H. Cho Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone Mol. Hum. Reprod., November 1, 2007; 13(11): 829 - 836. [Abstract] [Full Text] [PDF]

				B. E.J. Teunissen, P. J.H. Smeets, P. H.M. Willemsen, L. J. De Windt, G. J. Van der Vusse, and M. Van Bilsen Activation of PPAR{delta} inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts Cardiovasc Res, August 1, 2007; 75(3): 519 - 529. [Abstract] [Full Text] [PDF]

				M. Joner, A. Farb, Q. Cheng, A. V. Finn, E. Acampado, A. P. Burke, K. Skorija, W. Creighton, F. D. Kolodgie, H. K. Gold, et al. Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-{beta} and MCP-1 Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 182 - 189. [Abstract] [Full Text] [PDF]