cyclin-d1 and ciglitazone

PPARgamma levels in asthma- and non-asthma-derived airway smooth muscle cells and PPARgamma activation-induced cell proliferation were investigated. In the presence of FBS, PPARgamma levels were higher in subconfluent asthma-derived cells but lower in confluent cells compared with non-asthma-derived. However, PPARgamma activation did not alter cell proliferation.. Airway remodelling involves thickening of the airway smooth muscle (ASM) bulk. Proliferation of asthma-derived ASM cells is increased in vitro, but underlying mechanisms remain unknown. Peroxisome proliferators activated receptor-gamma (PPARgamma) regulates the cell cycle. It is suggested that PPARgamma agonists have anti-inflammatory effects, which may be valuable in the treatment of asthma, but information regarding their antiproliferative properties in ASM is lacking. Although corticosteroids reduce airway inflammation, in vitro they inhibit proliferation in only non-asthma ASM cells by reducing cyclin D1. We therefore investigated the effects of mitogenic stimulation (foetal bovine serum (FBS)), and a PPARgamma ligand (ciglitazone), on PPARgamma and cyclin D1 expression and proliferation of ASM cells. In addition, we examined the effects of ciglitazone on ASM cell proliferation.. We assessed PPARgamma and cyclin D1 mRNA and protein levels using quantitative PCR and immunoblotting. Cell proliferation was assessed using bromodeoxyuridine uptake.. In the presence of 5% FBS, PPARgamma and cyclin D1 expression decreased over time in non-asthmatic cells but increased in asthmatic cells (compared with sub-confluent cells). FBS-induced proliferation of asthmatic cells increased at all time points, but occurred only at day 7 with non-asthmatic cells (compared with unstimulated time-matched control). Ciglitazone increased PPARgamma expression in both groups, but did not alter cell proliferation, while fluticasone increased PPARgamma protein only in asthmatic cells.. Although in the presence of a mitogenic stimulus, PPARgamma was differentially expressed in asthma- and non-asthma-derived ASM; its expression was not related to the increased proliferation observed in asthmatic ASM.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Androstadienes; Asthma; Bronchi; Bronchodilator Agents; Cell Proliferation; Cells, Cultured; Cyclin D1; Female; Fluticasone; Humans; Male; Middle Aged; Mitogens; Myocytes, Smooth Muscle; PPAR gamma; RNA, Messenger; Thiazolidinediones; Young Adult

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to protect against stroke and improve neurological outcome after cerebral ischemia. This study investigated whether activation of cerebral PPARgamma improves recovery from focal cerebral ischemia by reducing expression of cyclin D1, which is associated with programmed neuron death. Focal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion (MCAO), followed by reperfusion. Intracerebroventricular (i.c.v.) infusion of the PPARgamma agonist ciglitazone, beginning 5 days before and continuing through 1 day after MCAO, reduced infarct size and cyclin D1 expression in the peri-infarct cortical region. Furthermore, primary cortical neurons treated with ciglitazone showed suppressed expression of cyclin D1 in response to hypoxia-reoxygenation. This protective effect was reversed after cotreatment with the selective PPAR-gamma antagonist GW 9662 (2-chloro-5-nitrobenzanilide), clearly demonstrating the involvement of a PPARgamma-dependent mechanism. Our data provide evidence that activation of neuronal PPARgamma makes a substantial contribution to neuroprotection by preventing cyclin D1 up-regulation in vitro and in vivo.

Topics: Animals; Brain Ischemia; Cell Survival; Cells, Cultured; Cerebral Cortex; Cyclin D1; Male; Neurons; Neuroprotective Agents; PPAR gamma; Rats; Rats, Sprague-Dawley; Thiazolidinediones

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Topics: Androgen-Binding Protein; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Dihydrotestosterone; Gene Expression; Genes, Reporter; Humans; Hypoglycemic Agents; Male; Mutation; Neoplasms, Hormone-Dependent; PPAR gamma; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; RNA, Small Interfering; Rosiglitazone; Thiazolidinediones; Transfection

Thiazolidinediones (TZDs) are peroxisome proliferator activated receptor gamma (PPARgamma) ligands that have been reported to reduce proliferation of human prostate cancer cells. However, the mechanisms by which TZDs inhibit prostate cancer cell proliferation are not fully understood. In addition, it is not known if the anti-proliferative effects of TZDs require activation of PPARgamma or are mediated by PPARgamma-independent pathways. The goals of this study were to assess whether TZDs regulate expression of proteins that control the transition from G1 to S phase of the cell cycle and define the role of PPARgamma in these TZD-induced responses in androgen-independent human prostate cancer cell lines. Western blot analysis revealed that growth inhibitory concentrations of the TZDs rosiglitazone and ciglitazone induced expression of the cyclin dependent kinase inhibitor p21 and decreased cyclin D1 levels in the androgen independent PC-3 cell line. Phosphorylation of retinoblastoma protein at Serine 780 was also reduced in PC-3 cells exposed to ciglitazone. Furthermore, growth inhibitory concentrations of ciglitazone increased p21 and lowered cyclin D1 expression within C4-2 cells. PPARgamma-directed siRNAs inhibited the ability of rosiglitazone to regulate expression of cyclin D1 and p21. However, knockdown of PPARgamma did not significantly reduce ciglitazone-induced alterations in cyclin D1 and p21. Furthermore PPARgamma siRNA did not prevent inhibition of PC-3 cell proliferation by either TZD. Thus, activation of PPARgamma is involved in rosiglitazone-induced alterations in cell cycle protein expression. However, the alterations in protein expression and proliferation induced by ciglitazone occur primarily via PPARgamma-independent signaling pathways.

Topics: Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Humans; Male; PPAR gamma; Prostatic Neoplasms; RNA, Small Interfering; Rosiglitazone; Signal Transduction; Thiazolidinediones

The effect and mechanism of the ciglitazone on lung cancer cells A549 growth in vitro and in vivo were studied. Various concentrations of ciglitazone were added to the cultured A549 line, and the proliferation and differentiation of A549 cells were examined by MTT and cytometry analysis. A549 cells (1 x 10(6)/mouse) were inoculated subcutaneously into 20 nude mice, which were randomly divided into two groups: the control group, the ciglitazone treated group. The weights of subcutaneous tumors were measured. The expression of cyclin D1 and P21 in the lung was detected by immohistochemistry and Western blot respectively. The results showed that the proliferation of A549 was inhibited significantly by ciglitazone in a dose- and time-dependent manner. There were more cells arrested in G1 /G0 phase and the expression of PPARgamma was markedly up-regulated in ciglitazone-treated group. Direct injection of ciglitazone into A549-induced tumors could suppress tumor growth in nude mice and the growth inhibitory rate was 36%. The expression of cyclin D1 was decreased and P21 increased significantly in ciglitazone-treated group as compared with control group. It was concluded that ciglitazone could inhibit A549 proliferation dose-dependently and time-dependently and induce differentiation, which might be related to the modulation of cell cycle interfered by PPARgamma.

Topics: Animals; Cell Proliferation; Cyclin D1; Humans; Lung Neoplasms; Mice; Mice, Nude; PPAR gamma; Random Allocation; Thiazolidinediones; Tumor Cells, Cultured

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal transition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)-gamma agonists have recently emerged as potential antineoplastic drugs. To establish whether ATC could be a target of PPAR gamma agonists, we first examined PPAR gamma protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPAR gamma agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones. PPAR gamma protein was present and functional in all ATC cell lines. Both ciglitazone and rosiglitazone showed complex biological effects in ATC cells, including inhibition of anchorage-dependent and -independent growth and migration, and increased apoptosis rate. Rosiglitazone-induced growth inhibition was associated with cell cycle arrest and changes in cell cycle regulators, such as an increase of cyclin-dependent kinases inhibitors p21(cip1) and p27(kip1), a decrease of cyclin D1, and inactivation of Rb protein. Rosiglitazone-induced apoptosis was associated with a decrease of Bcl-X(L) expression and caspase-3 and -7 activation. Moreover, rosiglitazone antagonized IGF-I biological effects by up-regulating phosphatase and tensin homolog deleted from chromosome 10 with subsequent inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway. Finally, rosiglitazone increased the expression of thyroid-specific differentiation markers. In conclusions, these data suggest that PPAR gamma agonists induce a partial reversion of the epithelial mesenchymal transition in ATC cells by multiple mechanisms. PPAR gamma agonists may, therefore, have a role in the multimodal therapy currently used to slow down ATC growth and dissemination.

Topics: Antineoplastic Agents; Apoptosis; bcl-X Protein; Carcinoma; Caspase 3; Caspase 7; Caspases; Cell Cycle; Cell Division; Cell Line, Tumor; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Epithelial Cells; Gene Expression; Humans; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Luciferases; Mesoderm; Phosphorylation; PPAR gamma; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Retinoblastoma Protein; RNA, Small Interfering; Rosiglitazone; Thiazolidinediones; Thyroid Neoplasms; Transfection

In light of the clinical relevance of targeting cyclin D1 in breast cancer, we have investigated the mechanism underlying the effect of the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists troglitazone and ciglitazone on cyclin D1 repression. We obtain evidence that the ability of high doses of troglitazone and ciglitazone to repress cyclin D1 is independent of PPARgamma activation. PPARgamma-inactive troglitazone and ciglitazone analogs 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione (Delta2-TG) and 5-[4-(1-methyl-cyclohexylmethoxy)-benzylidene]-thiazolidine-2,4-dione are able to facilitate cyclin D1 ablation with potency similar to that of troglitazone and ciglitazone in MCF-7 cells. Reverse transcription-polymerase chain reaction shows that the mRNA level of cyclin D1 remains unaltered in drug-treated cells, indicating the repression is mediated at the post-transcriptional level. Moreover, the ablative effect of these agents is specific to cyclin D1, in that the expression levels of many other cyclins and cyclin-dependent kinases examined remain unchanged after drug treatment. Our data indicate that troglitazone- and Delta2-TG-induced cyclin D1 repression is mediated via proteasome-facilitated proteolysis because it is inhibited by different proteasome inhibitors, including N-carbobenzoxy-l-leucinyl-l-leucinyl-l-norleucinal (MG132), lactacystin, and epoxomicin, and is preceded by increased ubiquitination. The dissociation of these two pharmacological activities (i.e., PPARgamma activation and cyclin D1 ablation) provides a molecular basis to use Delta2-TG as a scaffold to develop a novel class of cyclin D1-ablative agents. Therefore, a series of Delta2-TG derivatives have been synthesized. Among them, 5-[4-(6-allyoxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione represents a structurally optimized agent with potency that is an order of magnitude higher than that of Delta2-TG in cyclin D1 repression and MCF-7 cell growth inhibition.

Topics: Breast Neoplasms; Cell Line, Tumor; Chromans; Cyclin D1; Down-Regulation; Female; Humans; PPAR gamma; Proteasome Endopeptidase Complex; Thiazolidinediones; Troglitazone

Topics: Antineoplastic Agents; Apoptosis; Chromans; Cyclin D1; Humans; Lung Neoplasms; Prostaglandin D2; Proto-Oncogene Proteins p21(ras); Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazolidinediones; Transcription Factors; Troglitazone

To study the inhibitory effects of ciglitazone, a synthetic ligand of peroxisome proliferator-activated receptors (PPAR), on human lung cancer growth in vitro and in vivo and its mechanisms.. Human lung cancer A549 cells cultured in vitro were treated with different concentrations of ciglitazone. The proliferative activity and cell cycle of A549 cells were determined by MTT assay and flow cytometry. Expression of PPARgamma protein was detected by Western blot. A549 cells (1 x 10(6) cells/nude mouse) were inoculated subcutaneously into nude mice, which were randomly divided into two groups, 10 in each: control group (group A) and ciglitazone treated group (group B). When the tumors grew to a size with diameter around 1 cm, ciglitazone 100 microl (100 micromol/L) was intratumorally injected every other day in group B mice. A total of 15 injections were given. Mice in group A were similarly treated with normal saline. One month later, tumors were excised and weighed. Expression of cyclin D1 and p21 protein were detected by immunohistochemistry and Western blot.. Growth of A549 cells was significantly inhibited in group B in a dose-dependent and time-dependent fashion as compared with that in group A. Most of the ciglitazone-treated cells arrested in G(1)/G(0) phase and the expression of PPARgamma protein was markedly up-regulated. The tumor weights in group A was (2.79 +/- 0.33) g and that in group B was (1.51 +/- 0.40) g, with an inhibition rate of 47.0%. The expression level of cyclin D1 in group A was significantly higher than that in group B, while the expression level of p21 protein in group A was significantly lower than that in group B.. Ciglitazone can effectively inhibit the growth of human lung cancer A549 and induce its differentiation by cell cycle arrest via PPARgamma activation.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Female; G1 Phase; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; PPAR gamma; Random Allocation; Resting Phase, Cell Cycle; Thiazolidinediones; Time Factors

Treatment of MCF-7 cells with the peroxisome proliferator-activated receptor (PPAR) gamma agonists ciglitazone or 15-deoxy-Delta 12,14-prostaglandin J2 resulted in a concentration- and time-dependent decrease of cyclin D1 and estrogen receptor (ER) alpha proteins, and this was accompanied by decreased cell proliferation and G(1)-G(0)-->S-phase progression. Down-regulation of cyclin D1 and ER alpha by PPARgamma agonists was inhibited in cells cotreated with the proteasome inhibitors MG132 and PSII, but not in cells cotreated with the protease inhibitors calpain II and calpeptin. Moreover, after treatment of MCF-7 cells with 15-deoxy-Delta 12,14-prostaglandin J2 and immunoprecipitation with cyclin D1 or ER alpha antibodies, there was enhanced formation of ubiquitinated cyclin D1 and ER alpha bands. Thus, PPARgamma-induced inhibition of breast cancer cell growth is due, in part, to proteasome-dependent degradation of cyclin D1 (and ER alpha), and this pathway may be important for other cancer cell lines.

Topics: Breast Neoplasms; Cell Division; Cyclin D1; Cysteine Endopeptidases; Down-Regulation; Estrogen Receptor alpha; G1 Phase; Humans; Multienzyme Complexes; Prostaglandin D2; Proteasome Endopeptidase Complex; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; RNA, Messenger; S Phase; Thiazoles; Thiazolidinediones; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured; Ubiquitin

Mesangial proliferation is a key feature in the pathogenesis of a number of renal diseases and can be experimentally induced by the mitogen platelet-derived growth factor (PDGF). Mitogen-activated protein kinase (MAPK) signaling plays a key role in mesangial cell proliferation. In the present study we examined whether peroxisome proliferator-activated receptor gamma (PPARgamma) activators/ligands, thiazolidinediones such as ciglitazone, troglitazone, and rosiglitazone, can inhibit cell proliferation by modulating individual steps in the MAPK pathway.. Mouse mesangial cells were made quiescent and proliferation was measured following the application of PDGF. Using ciglitazone as the model compound, the mechanism of the antiproliferative effect of PPARgamma activators on MAPK and specific cell cycle regulatory proteins were examined by Western blot analysis and transfection studies.. Ciglitazone inhibited PDGF-induced mesangial cell proliferation in a dose-dependent manner (1 to 20 micromol/L). The inhibitory effect was blocked by a peroxisome proliferator-activated receptor element (PPRE) decoy oligonucleotide, indicating that the observed effect of ciglitazone was via PPARgamma activation. Ciglitazone (1 to 20 micromol/L) did not affect extracellular signal-regulated protein kinase (ERK) activation but inhibited the activation of serum response element (SRE) by 85 +/- 6% (P < 0.01). This effect was associated with a reduction in c-fos expression (80 +/- 9%, P < 0.01). Ciglitazone (1, 10, and 20 micromol/L) also inhibited cyclin D1 expression by 37 +/- 8%, 79 +/- 15%, and 87 +/- 12%, respectively (P < 0.001 to 0.001), and p21 expression by 45 +/- 6% (P < 0.01), 61 +/- 10% (P < 0.001), and 72 +/- 8% (P < 0.001), respectively. Ciglitazone inhibited PDGF-mediated up-regulation of p27. In addition, the antiproliferative effect of ciglitazone was potentiated by PD98059, a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor that acts at a step upstream from ERK.. These data indicate that PPARgamma activation may inhibit mesangial growth directly by affecting MAPK and cell cycle regulatory proteins. Furthermore, a MAP kinase inhibitor can potentiate the antiproliferative effect.

Topics: Animals; Cell Cycle Proteins; Cell Division; Cells, Cultured; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Drug Synergism; Enzyme Inhibitors; Flavonoids; Gene Expression; Gene Expression Regulation; Genes, fos; Glomerular Mesangium; Ligands; Mice; Mitogen-Activated Protein Kinases; Phosphorylation; Platelet-Derived Growth Factor; Receptors, Cytoplasmic and Nuclear; Serum Response Element; Thiazolidinediones; Transcription Factors; Tumor Suppressor Proteins

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in certain human cancers; ligand-induced PPARgamma activation can result in growth inhibition and differentiation in these cells. However, the precise mechanism for the antiproliferative effect of PPARgamma ligands is not entirely known.. The purpose of this study was to examine the effect of PPARgamma ligands on pancreatic cancer cell growth and invasiveness.. The effect of two PPARgamma ligands, 15 deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and ciglitazone, on the growth of four human pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, Panc-1, and L3.6) was assessed. Expression of cell-cycle and apoptotic-related proteins was measured. Finally, the effect of 15d-PGJ2 on pancreatic cancer cell invasiveness and matrix metalloproteinase expression was determined.. Both 15d-PGJ2 and ciglitazone inhibited the growth of all four pancreatic cancer cell lines in a dose- and time-dependent fashion. Treatment of BxPC-3 cells with 15d-PGJ2 resulted in a time-dependent decrease in cyclin D1 expression associated with a concomitant induction of p21waf1 and p27kip1. In addition, 15d-PGJ2 treatment induced apoptosis through activation of caspase-8, -9, and -3. Moreover, pancreatic cancer cell invasiveness was significantly suppressed after treatment with a nontoxic dose of 15d-PGJ2, which was associated with a reduction of MMP-2 and MMP-9 protein levels and activity.. These results demonstrate that PPARgamma ligands have the dual advantage of inhibiting pancreatic cancer cell growth while reducing the invasiveness of the tumor cells, suggesting a potential role for these agents in the adjuvant treatment of pancreatic cancer.

Topics: 3T3 Cells; Adenocarcinoma; alpha Catenin; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cadherins; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Cycle; Cell Cycle Proteins; Cell Division; Collagen; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Cyclooxygenase 2; Cytoskeletal Proteins; Drug Combinations; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Laminin; Ligands; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Membrane Proteins; Mice; Neoplasm Invasiveness; Neoplasm Proteins; Pancreatic Neoplasms; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Proteoglycans; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Trans-Activators; Transcription Factors; Tumor Cells, Cultured; Tumor Suppressor Proteins

The thiazolidenediones (TZDs) are commonly used to treat hyperglycemia in type 2 diabetes. Diabetes is associated with macrovascular disease, leading to accelerated atherosclerosis caused by aberrant vascular smooth muscle (VSM) cell proliferation. Although VSM cell proliferation is inhibited by the TZDs, the mechanism of this effect has not been established. Because of reports that the cyclin kinase inhibitors (CKIs) p21(Waf1/Cip1) and p27(Kip1) can exhibit both growth-inhibitory and growth-permissive effects in VSM cells, we asked whether alterations in these cell cycle regulatory proteins are the mechanism by which the TZDs inhibit VSM cell growth. We show that platelet-derived growth factor-BB increases p21 and p27 and that this increase is attenuated by TZDs. Surprisingly, when VSM cells were transfected with antisense oligodeoxynucleotides to p21 and p27, inhibition of DNA synthesis by TZDs occurred to the same degree as in control cells. Furthermore, the TZDs have inhibitory effects on cyclin D1 and cyclin E levels, suggesting another mechanism by which these drugs decrease VSM cell growth. These data suggest that the TZD-mediated reduction in CKI levels is not the sole mechanism for their antiproliferative effects. The observed decrease in levels of the G1 cyclins by the TZDs suggests a possible mechanism of VSM cell growth inhibition.

Topics: Animals; Becaplermin; CDC2-CDC28 Kinases; Cell Cycle Proteins; Cell Division; Cells, Cultured; Culture Media, Serum-Free; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; DNA; Enzyme Inhibitors; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Platelet-Derived Growth Factor; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Rats; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Suppressor Proteins