A non-thiazolidinedione partial peroxisome proliferator-activated receptor gamma ligand inhibits vascular smooth muscle cell growth.
Several peroxisome proliferator-activated receptor gamma (PPARgamma) agonists of the thiazolidinedione class inhibit vascular smooth muscle cell proliferation. It is not known whether the antiproliferative activity of PPARgamma agonists is limited to the thiazolidinedione class and/or is directly mediated through PPARgamma-dependent transactivation of target genes. We report here that a novel non-thiazolidinedione partial PPARgamma agonist (nTZDpa) attenuates rat aortic vascular smooth muscle cell proliferation. In a transfection assay for PPARgamma transcriptional activation, the non-thiazolidinedione partial PPARgamma agonist elicited approximately 25% of the maximal efficacy of the full PPARgamma agonist rosiglitazone. In the presence of the non-thiazolidinedione partial PPARgamma agonist, the transcriptional activity of the full agonist, rosiglitazone, was blunted, indicating that the non-thiazolidinedione partial PPARgamma agonist inhibits rosiglitazone-induced PPARgamma activity. The non-thiazolidinedione partial PPARgamma agonist (0.1-10 microM) inhibited vascular smooth muscle cell growth which was accompanied by an inhibition of retinoblastoma protein phosphorylation. Mitogen-induced downregulation of the cyclin-dependent kinase (CDK) inhibitor p27(kip1), and induction of the G1 cyclins cyclin D1, cyclin A, and cyclin E were also attenuated by the non-thiazolidinedione partial PPARgamma agonist. Maximal antiproliferative activity of the non-thiazolidinedione partial PPARgamma agonist required functional PPARgamma as adenovirus-mediated overexpression of a dominant-negative PPARgamma mutant partially reversed its inhibition of vascular smooth muscle cell growth. In contrast, overexpression of dominant-negative PPARgamma did not reverse the inhibitory effect of the non-thiazolidinedione partial PPARgamma agonist on cyclin D1. As the full PPARgamma agonist rosiglitazone exhibited no effect on cyclin D1, inhibition of that G1 cyclin by the non-thiazolidinedione partial PPARgamma agonist likely occurred through a PPARgamma-independent mechanism. These data demonstrate that a non-thiazolidinedione partial PPARgamma agonist may constitute a novel therapeutic for proliferative vascular diseases and could provide additional evidence for the important role of PPARgamma in regulating vascular smooth muscle cell proliferation.
Bruemmer
Dennis
D
Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California-Los Angeles, Warren Hall, Suite 24-130, 900 Veteran Avenue, Los Angeles, CA 90095-7073, USA.
Berger
Joel P
JP
Liu
Joey
J
Kintscher
Ulrich
U
Wakino
Shu
S
Fleck
Eckart
E
Moller
David E
DE
Law
Ronald E
RE
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D016193:G1 Phase / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D020128:Inhibitory Concentration 50; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019927:Cyclin E; D008024:Ligands; D008934:Mitogens; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C089946:2,4-thiazolidinedione; D008156:Luciferases