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At least 883 records · Page 49Linked to original sources
PubMed2006

PPARgamma-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma.

BACKGROUND: Although PPARgamma antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARgamma ligands induce PPARgamma-independent effects. There is a need to better define such effects to permit rational utilization of these agents. METHODS: We have studied the effects of a range of endogenous and synthetic PPARgamma ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2). RESULTS: 15-deoxy-prostaglandin J2 (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number; the selective PPARgamma antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis. CONCLUSION: Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARgamma-independent.

Antineoplastic Agents↗
PubMed2006

Regulators for blood glucose level affect gene expression of aquaporin 3.

Aquaporin 3 (AQP3), a membrane protein, is known to permeabilize water and other small molecules such as glycerol and urea and is localized in the bowel, skin, kidney, and erythrocytes. Since glycerol is a nutrient and serves as a source material in glycolytic metabolism, absorption of glycerol in the gastrointestinal tract may be under some control. Therefore we first investigated whether insulin regulating the glycolytic pathway took part in glycerol transport through AQP3 in the gastrointestinal tract and found that insulin significantly suppressed mRNA and protein expressions of AQP3 in Caco-2 cells. The antidiabetic drugs troglitazone and tolbutamide were also observed to suppress significantly AQP3 expression, but the biguanides metformin and buformin did not induce such suppression. Epinephrine was found to increase expression of AQP3, although glucagon showed no change of expression. Wortmannin and rapamycin were demonstrated to deactivate suppression of AQP3 expression by insulin and troglitazone, suggesting that the signal transducers, phosphoinositide 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR), are involved in the signal pathway for regulating transcription of AQP3.

Actins↗
PubMed1998

Human trabecular bone cells are able to express both osteoblastic and adipocytic phenotype: implications for osteopenic disorders.

The decrease in bone volume associated with osteoporosis and age-related osteopenia is accompanied by increased marrow adipose tissue formation. Reversal of this process may provide a novel therapeutic approach for osteopenic disorders. We have shown that cells cultured from human trabecular bone are not only osteogenic, but are able also to undergo adipocyte differentiation under defined culture conditions. Osteoblast differentiation was induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and adipocyte differentiation by dexamethasone (dex) plus 3-isobutyl-1-methylxanthine (IBMX) treatment. Adipogenesis was characterized by lineage-specific enzyme and gene activities, alpha-glycerophosphate-3-dehydrogenase activity, fatty acid binding protein, aP2 and lipoprotein lipase expression. Osteoblastogenesis was assessed by osteoblast characteristic 1,25(OH)2D3 induction of alkaline phosphatase activity and osteoblast-specific 1,25(OH)2D3-induced osteocalcin synthesis and release. We provide evidence for a common pluripotent mesenchymal stem cell that is able either to undergo adipogenesis or osteoblastogenesis, using clonal cell lines derived from human trabecular bone cell cultures. Adipogenesis can be induced also by long chain fatty acids and the thiazolidinedione troglitazone. Dex plus IBMX-induced adipogenesis can be inhibited by interleukin-1beta, tumor necrosis factor-alpha, and transforming growth factor-beta. Interestingly, and in contrast to extramedullary adipocyte differentiation as shown by mouse 3T3L-1 and a human liposarcoma SW872 cell line, trabecular bone adipogenesis was unaffected by insulin. Also, the formation of fully differentiated adipocytes from trabecular bone cells after troglitazone treatment and long chain fatty acids was dependent on increased expression of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma2 caused by dex plus IBMX. Specific inhibition of marrow adipogenesis and promotion of osteoblastogenesis of a common precursor cell may provide a novel therapeutic approach to the treatment of osteopenic disorders.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Pharmacological treatments for GH-induced insulin resistance.

Troglitazone (T) and d-chiroinositol (DCI) have been reported to improve insulin resistance associated with obesity and NIDDM. We tested whether these compounds counteract the insulin antagonistic effects of recombinant human GH. Male Wistar rats were allocated to 4 different treatment groups, rhGH (n=8), rhGH+T (n=7), rhGH+DCI (n=8) and control (saline, n=8). rhGH (2 IU/100 g/day) was injected sc twice daily for 2 days. T and DCI were given (20 mg/day) po for 5 days preceding and 2 days along with rhGH. Euglycemic hyperinsulinemic clamp studies were done to assess the hepatic glucose output (HGO) and glucose disappearance rate (GDR). Fasting plasma glucose, insulin, serum FFA and basal HGO were similar in all 4 treatment groups. During the hyperinsulinemic clamp which raised plasma insulin levels to 7.2 +/- 0.4 ng/ml, HGO was suppressed in the control and rhGH+T treated rats but not in the rats treated with rhGH and rhGH+DCI. GDR decreased in the rats which received rhGH (18.1 +/- 5.8 vs 30.3 +/- 5.2 mg/kg/min) compared to the control rats. The rats given either T (24.7 +/- 2.7) or DCI (31.4 +/- 2.7) along with rhGH showed comparable GDR to the control rats. These results indicated that rhGH induced hepatic and peripheral insulin resistance. Troglitazone counteracted the insulin-antagonistic action of rhGH both in the liver and the peripheral tissues. DCI was effective in offsetting peripheral insulin resistance but without any effect on hepatic insulin resistance associated with rhGH treatment.

Animals↗
PubMed2000

Thiazolidinediones inhibit the expression of beta3-adrenergic receptors at a transcriptional level.

The effect of the thiazolidinediones (TZDs) darglitazone and troglitazone on beta3-adrenergic receptor (AR) expression was studied in cultured cell lines representing several tissues. After 24 h of exposing HIB-1B brown adipocytes to 30 micromol/l darglitazone or 20 micromol/l troglitazone, beta3-AR mRNA levels were reduced by 75%. This effect was significant within 1 h of exposure to a maximal dose of these drugs, with the full effect obtained within 10 h. The darglitazone ID50 was approximately 10 nmol/l, similar to the Kd of TZDs binding to peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These drugs also decreased beta3-AR mRNA in 3T3-F442A white adipocytes, but not in SK-N-MC cells, which lack PPAR-gamma2. A luciferase reporter gene containing 1.4 kb of 5' flanking sequence of the mouse beta3-AR was transiently transfected, with or without PPAR-gamma2, in SK-N-MC cells. The vigorous expression of luciferase driven by the beta3-AR gene sequence was inhibited by TZDs in a PPAR-gamma2-dependent manner. The half-lives of gamma3-AR precursor RNA and mRNA were short, approximately 40 and approximately 100 min, respectively, and remained unaffected by TZD treatment. Exposure of HIB-1B cells to 30 micromol/l darglitazone was associated with reduced beta3-AR mRNA levels, as well as decreased response of uncoupling protein 1 to norepinephrine + propranolol (a beta1 beta2-AR antagonist) or the specific beta3-AR agonist CL 316, 243. Both the beta3-AR mRNA level and response to these stimuli fully recovered by 24 h of removing the drug, indicating that the beta3-AR protein and its coupling to adenylyl cyclase rapidly followed the changes in mRNA. Thus, TZDs can rapidly reduce beta3-AR expression at the transcriptional level, acting through PPAR-gamma2. The rapid turnover and responses of beta3-AR to perturbations, along with numerous other factors reported to regulate its expression, suggest a tight control of beta3-AR and function. Lastly, leptin being the only other known gene suppressed by TZDs, the present studies support a concerted lipogenic effect of these drugs.

3T3 Cells↗
PubMed2002

C(2)-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 adipocytes.

Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of tumor necrosis factor (TNF)-alpha is thought to be one of the mechanisms by which TNF-alpha induces insulin resistance. Ceramide is the suggested second messenger of TNF-alpha action, and in this study, we used 3T3-L1 adipocytes to investigate the effects of C(2)-ceramide (a short-chain ceramide analog) on the expression and regulation of PDE3B and lipolysis. Incubation of adipocytes with 100 micromol/l C(2)-ceramide (N-acetyl-sphingosine) resulted in a time-dependent decrease of PDE3B activity, accompanied by decreased PDE3B protein expression. C(2)-ceramide, in a time- and dose-dependent manner, stimulated lipolysis, an effect that was blocked by H-89, an inhibitor of protein kinase A. These ceramide effects were prevented by 20 micromol/l troglitazone, an antidiabetic drug. In addition to downregulation of PDE3B, the antilipolytic action of insulin was decreased by ceramide treatment. These results, together with data from other studies on PDE3B and lipolysis in diabetic humans and animals, suggest a novel pathway by which ceramide induces insulin resistance. Furthermore, PDE3B is demonstrated to be a target for troglitazone action in adipocytes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells.

Thiazolidinediones, synthetic ligands of peroxisomal proliferator-activated receptor-gamma (PPAR-gamma), improve peripheral insulin sensitivity and glucose-stimulated insulin secretion in pancreatic beta-cells. To explore the role of PPAR-gamma in glucose sensing of beta-cells, we have dissected the beta-cell-specific glucokinase (betaGK) promoter, which constitutes glucose-sensing apparatus in pancreatic beta-cells, and identified a peroxisomal proliferator response element (PPRE) in the promoter. The betaGK-PPRE is located in the region between +47 and +68 bp. PPAR-gamma/retinoid X receptor-alpha heterodimer binds to the element and activates the betaGK promoter. The betaGK promoter lacking or having mutations in PPRE cannot be activated by PPAR-gamma. PPAR-gamma activates the betaGK promoter in beta-cells as well as non-beta-cells. Furthermore, troglitazone increases endogenous GK expression and its enzyme activity in beta-cell lines. These results indicate that PPAR-gamma can regulate GK expression in beta-cells. Taking these results together with our previous work, we conclude that PPAR-gamma regulates gene expression of glucose-sensing apparatus and thereby improves glucose-sensing ability of beta-cells, contributing to the restoration of beta-cell function in type 2 diabetic subjects by troglitazone.

Animals↗
PubMed2003

Nocturnal and postprandial free fatty acid kinetics in normal and type 2 diabetic subjects: effects of insulin sensitization therapy.

Whether free fatty acid (FFA) rate of appearance (R(a)) is increased in type 2 diabetes is controversial. To characterize nocturnal and postprandial abnormalities in FFA kinetics and to determine the effects of treatment with insulin sensitizers on lipolysis, we measured palmitate R(a) in control subjects (n = 6) and individuals with poorly controlled, sulfonylurea-treated type 2 diabetes (HbA(1c) = 8.7 +/- 0.2%, n = 20), the latter before and at the end of 12 weeks of treatment with troglitazone (600 mg/day, n = 4), metformin ( approximately 2,000 mg/day, n = 8), or placebo (n = 8). Subjects consumed a standard breakfast at 0800 h. Results in control subjects and type 2 diabetic subjects were compared at baseline. Integrated nocturnal FFA R(a) (AUC(1:00-8:00 A.M.)) was approximately 50% higher in type 2 diabetic subjects than in control subjects (29.4 +/- 3.0 vs. 19.4 +/- 3.9 mmol. m(-2). 7 h(-1), respectively, P < 0.05), whereas postprandial palmitate R(a) (AUC(0-240 min)) was almost threefold higher in type 2 diabetic subjects than in control subjects (14.2 +/- 1.7 vs. 5.3 +/- 1.0 mmol. m(-2). 4 h(-1), respectively, P < 0.01). After troglitazone treatment, nocturnal palmitate R(a) did not change, but postprandial palmitate R(a) decreased by approximately 30% (P < 0.05). Palmitate kinetics did not change with metformin or placebo treatment. In summary, nocturnal and postprandial FFA R(a) is increased in type 2 diabetes. Postprandial lipolysis appears to be preferentially improved by thiazolidinediones compared with nocturnal lipolysis.

Adult↗
PubMedDate not supplied

An update on the Diabetes Prevention Program.

OBJECTIVE: To summarize the results of the Diabetes Prevention Program (DPP) and describe the additional 5-year follow-up study. METHODS: The design, implementation, and outcome of the DPP are reviewed, and an economic analysis of the effects of diabetes prevention and delay is presented. RESULTS: The DPP, thus far the largest diabetes prevention trial with the most ethnically diverse patient population, originally consisted of more than 3,800 subjects with impaired glucose tolerance. These subjects were randomized to receive one of four interventions: intensive lifestyle adjustments or standard lifestyle plus one of the following--placebo, metformin, or troglitazone. In June 1998, the troglitazone treatment was discontinued after a fatal case of liver failure in a study participant, but the subjects in this arm of the study continued to undergo followup. Thus, 3,234 subjects remained in the other three arms of the study. After a mean of 2.8 years of follow-up, the DPP was prematurely terminated because of an observed significant benefit to the intervention groups. Both metformin therapy and intensive lifestyle intervention reduced the risk of developing diabetes (by 31% and 58%, respectively, in comparison with placebo), and both interventions were deemed to be cost-effective on the basis of computer projections over a lifetime. Because of the premature discontinuation of the DPP, the durability of the interventions on diabetes prevention and the effect on microvascular and macrovascular disease could not be assessed. The subsequent outcomes study will address these issues during a 5-year follow-up period. CONCLUSION: The DPP showed that both metformin and intensive lifestyle modifications effectively delayed or prevented the development of diabetes in a cost-effective manner.

Adult↗
PubMedDate not supplied

Use of insulin-sensitizing agents in patients with polycystic ovary syndrome.

OBJECTIVE: To review the subject of polycystic ovary syndrome and the therapeutic use of insulin-sensitizing agents in patients with this endocrinopathy. METHODS: We present background information on this disorder and summarize the pertinent published literature. RESULTS: Polycystic ovary syndrome affects approximately 7.5% of reproductive-age women in the United States. Although specific diagnostic criteria for this condition have not been established, the presence of three major factors-chronic anovulation, hyperandrogenemia, and clinical signs of hyperandrogenism-has been proposed as essential for consideration of the diagnosis. A high ratio of serum luteinizing hormone to follicle-stimulating hormone is found in 60 to 75% of women with this syndrome. Treatment with metformin may yield heterogeneous responses in differing populations with polycystic ovary syndrome, but most studies have shown evidence of restoration of ovulatory cycling. In addition, weight loss and decreases in free and total testosterone levels have been reported. Troglitazone therapy proved somewhat less efficacious than metformin for restoring menstrual cycles and similar to metformin in producing hormonal responses. Because troglitazone is no longer available for clinical use, studies will need to be extended to other thiazolidinediones. Patients treated with another insulin sensitizer, D-chiro-inositol, have demonstrated improved insulin sensitivity, ovulatory rates, and biochemical findings. CONCLUSION: Current evidence suggests that the use of insulin-sensitizing agents in patients with polycystic ovary syndrome not only improves their sensitivity to the effects of insulin on glucose and lipid metabolism but also ameliorates clinical and biochemical manifestations of hyperandrogenism and increases rates of ovulation. Multicenter studies with larger numbers of patients are needed.

Androgens↗
PubMed2000

[Insulin sensitizer and hypertension].

Insulin resistance syndrome is the theory that glucose intolerance, hyperinsulinemia, increased very low density lipoprotein triglyceride level, decreased high density lipoprotein cholesterol level, and hypertension are proposed consequences of insulin resistance. In this theory, insulin resistance and the resultant hyperinsulinemia are considered to raise blood pressure through 1) sympathetic nervous system activation, 2) renal sodium retention, 3) renin-angiotensin system stimulation, and 4) intracellular calcium accumulation in vascular smooth muscle. Indeed, metabolic disturbance and insulin resistance have been pointed out in essential hypertensives. The effect of insulin sensitizer on blood pressure have been investigated in human and animal experiments. It has been clarified that troglitazone reduces blood pressure in essential hypertensives and fructose fed rats. However, it has also been reported that troglitazone did not lower blood pressure in SHR and fructose fed rats. Further study will be necessary to clarify the effects of insulin sensitizer on blood pressure.

Animals↗
PubMed2000

[Kidney disease and insulin resistance--clinical impact of thiazolidinedione compounds for kidney disease].

The thiazolidinedione compounds are well known hypoglycemic agents via increasing insulin-sensitivity. Herein, we provide the possibility that thiazolidinedione compounds could be useful for renal dysfunction through mechanism dependent or independent of its insulin-sensitizing action. In type 2 diabetes, troglitazone could reduce urinary albumin-creatinine ratio compared to metformin. Furthermore, we have shown that troglitazone was able to prevent diabetic glomerular dysfunction through inhibition of diacylglycerol-protein kinase C-extracellular signal-regulated kinase pathway in type 1 diabetic rats. Thus, thiazolidinediones might be effective agents for treating insulin-resistant diabetes as well as diabetes-induced kidney disease.

Animals↗
PubMed2000

[Insulin sensitizer. A new therapy option for type 2 diabetic patients].

The glitazones, also known as insulin sensitizers, represent a new concept in the treatment of type 2 diabetes. While previously available antidiabetics have no influence on an existing insulin resistance, the glitazones act directly on the receptors in the muscles, fatty tissue and liver, and in this way reduce insulin resistance. To date, three members of this group of substances are known: troglitazone, rosiglitazone and pioglitazone. In a study done to investigate pioglitazone, fasting blood sugar and HbA1c achieved virtually normal values, and lipid metabolism also improved. On the basis of the results of studies done to date, the tolerability of both pioglitazone and rosiglitazone is good. In contrast to troglitazone, no evidence has been found for a hepatotoxic effect. Insulin sensitizers do not cause hypoglycemia, since they do not stimulate the pancreas. They are suitable both for monotherapy and combination treatment with metformin, sulfonylureas and insulin.

Chromans↗
PubMed2003

[The effect of peroxisome proliferator-activated receptor alpha and gamma ligands on free fatty acid-induced INS-1 cell impairment].

OBJECTIVE: To investigate the effect of peroxisome proliferator-activated receptor alpha and gamma (PPARalpha and PPARgamma) ligands on free fatty acid (FFA)-induced pancreatic beta-cell impairment. METHODS: Insulinoma cell line beta-cell (INS-1 cells) were treated with PPARalpha ligand (clofibrate) and PPARgamma ligands (troglitazone and thiazolidinedione). C, N diphenyl-N'-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) viability assay and DNA fragmentation analysis were used to evaluate the effect of PPARalpha and PPARgamma ligands on FFA-induced INS-1 cell impairment. RESULTS: The viability of INS-1 cells decreased after incubation of the cells with FFA (0.25 - 1 mmol/L) for 24 hours. FFA (1 mmol/L) was also found to induce INS-1 cell apoptosis. Comparison of the cells treated with or without clofibrate (100 micro mol/L), troglitazone (10 micro mol/L) and thiazolidinedione (100 micro mol/L), we found that these PPARalpha and PPARgamma ligands could protect INS-1 cells from the cytotoxicity of FFA, including lipoapoptosis. CONCLUSION: FFA mediates significant lipotoxicity and lipoapoptosis in beta-cells and application of PPARalpha and PPARgamma ligands might be of value in protection of beta-cells from FFA cytotoxicity.

Animals↗
PubMed2004

Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510.

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), 15-deoxy-delta(12,14)-prostaglandin J2, troglitazone, and rosiglitazone increased PPARgamma and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARgamma ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARgamma ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

Angiogenesis Inhibitors↗
PubMed2005

Relationship between peroxisome proliferator-activated receptor-gamma expression and differentiation of human esophageal squamous cell carcinoma.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is involved in suppressing the growth of several tumors. We showed that PPAR-gamma is expressed in Barrett's adenocarcinoma cell lines and inhibited the growth of these lines through the induction of G1 cell cycle arrest and apoptosis. We examined PPAR-gamma expression in human esophageal squamous cell carcinoma (SCC) in vitro and in vivo and investigated whether PPAR-gamma ligands affect the proliferation and apoptosis of human SCC cell lines. Biopsy specimens (n=46) obtained from human SCC of the esophagus were stained using a monoclonal antibody against human PPAR-gamma. We assessed the effects of PPAR-gamma ligands on the growth of SCC cells by adding 15-deoxy prostaglandin J2 (15d-PGJ2), or troglitazone to six human esophageal SCC cell lines (TE-1, TE-2, TE-3, TE-5, TE-8, and TE-9). Immunohistochemical staining showed that 34 of 46 (73.9%) SCC of the esophagus expressed PPAR-gamma. All SCC cell lines expressed PPAR-gamma mRNA and protein, especially when poorly differentiated (TE-2, TE-5, and TE-9). The PPAR-gamma ligands significantly and dose-dependently inhibited the proliferation of SCC lines, except for well-differentiated TE-1 and TE-3. Apoptosis was induced by 15d-PGJ2 (10 microM) in all tested SCC lines except TE-1, whereas troglitazone (50 microM) was marginally effective in only the TE-2 and TE-3 cell lines. The present findings suggest that PPAR-gamma could be a therapeutic target for treating squamous cell carcinoma of the esophagus, possibly through the induction of apoptosis.

Antibodies, Monoclonal↗
PubMed2006

Effects of PPAR and RXR ligands in semaphorin 6B gene expression of human MCF-7 breast cancer cells.

This study tests the hypothesis that the activators of peroxisome proliferator-activated receptors (PPARs) and 9-cis-retinoic acid receptor (RXR) regulate human semaphorin 6B (Sema6B) gene expression. The human MCF-7 breast adenocarcinoma cell line was chosen because it expresses Sema6B at a high level. The Sema6B mRNA level was analyzed by RT-PCR and the semaphorin 6B protein content was determined using a polyclonal antibody that we have produced and characterized. Treatments with fenofibrate (a PPARalpha activator) and troglitazone (a PPARgamma ligand) strongly decreased the Sema6B mRNA. The drop in Sema6B mRNA level and in protein content was more important when the treatment combined the action of fenofibrate or troglitazone and 9-cis-retinoic acid. On the other hand, no significant change was observed in the Sema6B mRNA and protein levels when the cells were exposed to the combined action of GW610742 (a PPARbeta activator) and 9-cis-retinoic acid. These data suggest that PPARalpha/RXR and PPARgamma/RXR heterodimers are involved in the regulation of Sema6B gene expression and open new perspectives concerning the participation of these nuclear receptors in cell recognition and migration.

Humans↗
PubMed1997

Effects of thiazolidinediones on growth and differentiation of human aorta and coronary myocytes.

Thiazolidinediones, insulin-sensitizing agents that lower insulin and lipid levels in insulin-resistant states, block agonist-induced Ca2+ entry into vascular smooth muscle (VSM) cells in vitro and lower blood pressure in animals and humans in vivo. In this study, we investigated the effects of ciglitazone and troglitazone on cell growth and DNA synthesis (as thymidine incorporation), and differentiation in cultured human aorta (haVSM) and human coronary artery (hcaVSM) VSM cells. Mitotically quiescent haVSM cells were stimulated with serum or platelet-derived growth factor (PDGF). Ciglitazone (40 micromol/L) inhibited haVSM cell proliferation by 84 +/- 16% (mean +/- SEM) (P < .05, n = 3), and serum and PDGF stimulated [3H]-thymidine incorporation by 91 +/- 18% (P < .03, n = 3) and 73 +/- 14% (P < .03, n = 4), respectively. Troglitazone (5 micromol/L) inhibited proliferation of haVSM cells by 78 +/- 14% (P < .05, n = 3) and hcaVSM cells by 91 +/- 18% (P < .05, n = 3). Proliferating VSM cells (synthetic phenotype) expressed small amounts of alpha-actin, whereas nonproliferating VSM cells (contractile phenotype) exhibited abundant alpha-actin. Exposure of proliferating haVSM cells to 40 micromol/L ciglitazone induced a marked increase in alpha-actin staining, consistent with transition to the well differentiated, contractile phenotype. To the extent that thiazolidinediones similarly affect growth factor-induced proliferation and differentiation of arterial myocytes in vivo, these agents may be useful in treating atherosclerosis and in preventing restenosis after angioplasty.

Aorta↗