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PubMed2002

Troglitazone treatment increases protein kinase B phosphorylation in skeletal muscle of normoglycemic subjects at risk for the development of type 2 diabetes.

We investigated whether the effect of troglitazone on glucose disposal is associated with altered insulin signaling. Nondiabetic first-degree relatives of type 2 diabetic patients (age 30 +/- 2 years, BMI 30 +/- 1 kg/m(2); n = 20) were randomized in a double-blind manner to 3 months of troglitazone (200 mg/day) or placebo treatment. Before and after treatment, 3-h euglycemic-hyperinsulinemic glucose clamps (40 mU. m(-2). min(-1)) were performed, and muscle biopsies were obtained immediately before and after the clamps. In the biopsies, insulin receptor kinase (IRK) activity, insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity, Ser(473) and Thr(308) phosphorylation of protein kinase B (PKB), and protein expression of IRS-1, IRS-2, phosphoinositol-dependent kinase-1 (PDK-1), PKB, and GLUT-4 were determined. After troglitazone treatment, insulin-stimulated glucose disposal was increased compared with pretreatment and placebo (279 +/- 37 vs. 211 +/- 26 and 200 +/- 25 mg. m(-2). min(-1); both P < 0.05). IRK and PI3K activities were not altered by troglitazone, but PKB Ser(473) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level (138 +/- 36 vs. 77 +/- 16 and 55 +/- 13 internal standard units; both P < 0.05) and with pretreatment at the basal level (31 +/- 9 vs. 14 +/- 4 internal standard units; P < 0.05). PKB Thr(308) phosphorylation also tended to be higher, but this was not statistically significant. Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1999

The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity.

The adhesion of monocytes to endothelium, an early event in atherosclerosis, is mediated by cell adhesion molecules. Signal-transduction pathways for these binding molecules include the translocation of the transcription factor NF-kappaB; moreover, intracellularly generated oxygen-derived free radicals (ODFR) play a major role in this process. This study evaluated the extent to which troglitazone, an oral antidiabetic agent with antioxidant properties, affects the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells (HUVECs), induced by different prooxidant signals such as oxidized LDL and tumor necrosis factor-alpha (TNF-alpha). Furthermore we assessed whether the NF-kappaB activation is modulated by the antioxidative effect of troglitazone. Oxidized LDL not only caused a dose-dependent increase of ICAM-1, VCAM-1 and E-selectin (p<0.001), but also synergically increased their TNF-alpha-induced expression (p<0.001). Troglitazone reduced in a dose-dependent manner the expression of VCAM-1, ICAM-1 and E-selectin induced by different amounts of oxidized LDL (p<0.001). The addition of troglitazone to HUVECs significantly reduced the expression of ICAM-1, VCAM-1 and E-selectin induced by TNF-alpha alone or in combination with oxidized LDL (p<0.001); this reduction was paralleled by a significant fall in NF-kappaB translocation. The results suggest that troglitazone may have prevented NF-kappaB-mediated adhesion molecule expression by exerting its antioxidant effect on ODFR.

Antioxidants↗
PubMedDate not supplied

Substitution of pioglitazone for troglitazone in patients with type 2 diabetes.

OBJECTIVE: To evaluate the clinical utility of pioglitazone therapy in patients who previously received troglitazone. METHODS: We undertook an observational study involving patients with type 2 diabetes, who were originally treated with troglitazone and subsequently converted to pioglitazone therapy. Drug efficacy was evaluated by comparing baseline hemoglobin A1c (HbA1c) levels, weight, blood pressure, and lipid profiles (during troglitazone treatment) with corresponding values 6 months after final pioglitazone dose titration. Drug safety was evaluated by review of hepatic enzyme levels and documented reports of side effects. RESULTS: The study cohort consisted of 316 patients in whom pioglitazone therapy was initiated after they had received troglitazone for at least 1 year. Discontinuation of pioglitazone treatment subsequently occurred in 43 patients; in 7 additional patients, no follow-up occurred. We found no significant difference between baseline and follow-up mean HbA1c values. Aspartate aminotransferase levels did not significantly change after 6 months of pioglitazone therapy; however, alanine aminotransferase levels increased by a statistically significant 3.8 U/L (95% confidence interval, 2.6 to 4.9). Pioglitazone treatment was discontinued because of edema in 29 of the 309 evaluable patients (9.4%). CONCLUSION: Pioglitazone was as effective as troglitazone in maintaining HbA1c levels. The hepatic safety of pioglitazone was also demonstrated.

Aged↗
PubMed1999

Troglitazone or metformin in combination with sulfonylureas for patients with type 2 diabetes?

BACKGROUND: Combination oral therapy is often used to control the hyperglycemia of patients with type 2 diabetes. We compared the effectiveness of metformin and troglitazone when added to sulfonylurea therapy for patients with type 2 diabetes who had suboptimal blood glucose control. METHODS: We used a randomized 2-group design to compare the efficacy, safety, and tolerability of troglitazone and metformin for patients with type 2 diabetes mellitus that was inadequately controlled with diet and oral sulfonylureas. Thirty-two subjects were randomized to receive either troglitazone or metformin for 14 weeks, including a 2-week drug-titration period. The primary outcome variable was mean change in the level of glycosylated hemoglobin (Hb A1c) from baseline. Secondary outcomes included mean changes from baseline in fasting plasma glucose and C-peptide levels, renal or metabolic side effects, and symptomatic tolerability. RESULTS: The addition of either troglitazone or metformin to oral sulfonylurea therapy significantly decreased Hb A1c levels. Both treatment regimens also significantly reduced fasting plasma glucose and C-peptide levels. We found no significant differences between the treatment arms in efficacy, metabolic side effects, or tolerability. CONCLUSIONS: Our results demonstrate that troglitazone and metformin each significantly improved Hb A1c, fasting plasma glucose, and C-peptide levels when added to oral sulfonylurea therapy for patients with type 2 diabetes who had inadequate glucose control.

Adult↗
PubMed2001

Case of the month. Hepatic and renal failure in a patient taking troglitazone and metformin.

Troglitazone is a thiazolidinedione with insulin-sensitizing activities when administered to humans or animals with type 2 diabetes mellitus. It has been shown to have numerous desirable metabolic effects on glucose and lipid metabolism. A major adverse effect of troglitazone is the development of hepatotoxicity. In early clinical trials, elevations of serum aminotransferases (> 3 times upper normal limit) occurred in 48 of 2510 (1.9%) subjects receiving troglitazone. In December 1997 and again in August 1998, the United States Food and Drug Administration issued stronger warnings after getting reports of more than a hundred cases of liver damage, including liver failure requiring transplantation in three patients and death in another patient. Warner-Lambert Company announced on March 21, 2000 that it is voluntarily discontinuing the sale of Rezulin (troglitazone) tablets for the treatment of type 2 diabetes. Media reports sensationalizing the risks, associated with Rezulin therapy had created an environment in which patients and physicians were simply unable to make well-informed decisions regarding the safety and efficacy of Rezulin. Under these circumstances, and after discussions with the FDA, the company decided it was in the best interests of patients to discontinue marketing Rezulin. Concerns about the hepatotoxicity of troglitazone led the Medicine Control Agency of the United Kingdom to request voluntary withdrawal of the drug from the UK in December 1997.

Acute Kidney Injury↗
PubMedDate not supplied

Induction mechanism of apoptosis by troglitazone through peroxisome proliferator-activated receptor-gamma in gastric carcinoma cells.

BACKGROUND: It has been reported recently that the antidiabetic thiazolidinediones not only induce fibroblast differentiation but also inhibit the growth of carcinoma cells. MATERIALS AND METHODS: In the present study, in order to elucidate the further mechanism of growth inhibition by troglitazone, the expression of cell cycle regulators and apoptotic regulators were examined by cDNA microarrays and Western blot analysis by gastric carcinoma cells. RESULTS: Six gastric carcinoma cell lines (TMK-1, MKN-1,7,28,45,74) were treated with 0.1, 1, 10, 100 microM of troglitazone in vitro. The growth of 5 cell lines were inhibited by troglitazone in a time- and dose-dependent manner. Interestingly, the expression of cyclin D mRNA and protein was decreased and that of p27 was increased in TMK-1 cells at 12 hours after troglitazone treatment, suggesting the induction of cell cycle arrest of the cells. On the other hand, DNA ladder formation was observed at 12 hours after treatment. Moreover, the expression of cytochrome C, caspases 3 and 8 and PARP genes was increased after treatment and the gradual reduction of Bcl-XL protein was observed, which indicate that the apoptotic signals were induced after treatment by troglitazone. CONCLUSION: These results suggest that the thiazolidinediones can be a new therapeutic tool for gastric carcinoma via cell cycle regulation and apoptosis.

Antineoplastic Agents↗
PubMedDate not supplied

Troglitazone in type II diabetes mellitus.

Troglitazone, a new antihyperglycemic agent, is approved for use alone, with oral sulfonylureas, or with insulin in the treatment of type II diabetes mellitus. Rather than stimulating insulin secretion, it enhances insulin sensitivity. Potential advantages of troglitazone over oral sulfonylureas include decreased endogenous insulin concentrations, decreased exogenous insulin requirements, reduced hypoglycemic risk, and convenient once/day administration. The effect on morbidity and mortality from lowering endogenous and exogenous insulin concentrations remains to be determined. Troglitazone also has potential disadvantages. It induces cytochrome P450 isoenzyme 3A4, although few drug interactions have been identified to date. Serum transaminases must be monitored routinely because of rarely reported cases of idiosyncratic hepatocellular injury. In addition, the cost of troglitazone is much higher than that of other oral antihyperglycemic agents or insulin. Given the available information, troglitazone has limited benefit over oral sulfonylureas or metformin as monotherapy or in combination with oral sulfonylureas. Until additional combination and comparative studies have been done, the agent should be reserved for patients with poor glycemic control receiving high daily doses of insulin.

Chromans↗
PubMed1998

Troglitazone reduces free fatty acid-induced insulin resistance in perfused rat hindquarter.

In order to study the effects of troglitazone on insulin resistance associated with elevated plasma free fatty acid (FFA), the hindquarters of rats treated with troglitazone for 14 days were perfused with a medium containing 15 mmol/l glucose, 0-1,000 microU/ml insulin, and 0 or 1.0 mmol/l palmitate. In the absence of palmitate, net glucose uptake was similar between control and troglitazone-treated rat hindquarters at each insulin concentration: 47 +/- 10 and 45 +/- 9 mumol for 30 min at 0 microU/ml insulin; and 94 +/- 14 and 99 +/- 13 mumol for 30 min at 1,000 microU/ml insulin respectively. Addition of palmitate abolished insulin stimulation of net glucose uptake in control rat hindquarter but did not decrease it in troglitazone-treated rat hindquarter (60 +/- 11 vs 99 +/- 12 mumol for 30 min at 1,000 microU/ml insulin, p < 0.01). It is suggested that the "FFA-tolerant effect" is one mechanism by which troglitazone reduces insulin resistance.

Animals↗
PubMed2003

Association of troglitazone-induced liver injury with mutation of the cytochrome P450 2C19 gene.

An anti-diabetic agent, troglitazone, was withdrawn from the market because of its association with liver injury. However, the mechanism of the injury has not been elucidated. We examined, retrospectively, the frequency of the polymorphisms of the cytochrome P450 (CYP) 2C19 and 2D6 genes in eight patients with type 2 diabetes who had troglitazone-induced liver injury and 31 subjects who tolerated troglitazone well. Polymorphisms of CYP 2C19 and 2D6 genes were analyzed by polymerase chain reaction using peripheral white blood cells. The incidence of mutations was compared with known population data for the Japanese. Homozygous or compound heterozygous mutations in CYP 2C19 alleles were found in four of the eight (50.0%) patients with troglitazone-induced liver injury. This rate was significantly higher than that in patients without liver injury (four of 31, 12.9%). The frequency of P450 2D6 mutations was the same in both groups. In conclusion, troglitazone-induced liver injury occurred more frequently in subjects with the CYP 2C19 mutations in Japanese patients.

Journal Article↗
PubMedDate not supplied

Troglitazone: current therapeutic role in type 2 diabetes mellitus.

OBJECTIVE: To describe the role of troglitazone in the treatment of non-insulin-dependent diabetes mellitus. METHODS: The potential mechanisms of action of the thiazolidinediones are outlined, and studies that have been conducted in animals and in humans are reviewed. RESULTS: Although the precise mode of action of troglitazone, a thiazolidinedione, is unknown, this agent is an insulin sensitizer that has been shown to decrease fasting insulin, fasting plasma glucose, and blood pressure levels in humans. The effect of troglitazone is progressively greater over time; in several studies, the maximal action occurred as long as 12 weeks after initiation of treatment. The usual daily dose is 200 to 600 mg, and no dosage adjustment is necessary in patients with renal insufficiency. Adverse events, including fluid retention and hepatic dysfunction, may limit the utility of troglitazone in some clinical situations. CONCLUSION: Both in monotherapy and in combination with sulfonylureas, insulin, or metformin, troglitazone has proved to be an effective agent for the treatment of type 2 diabetes mellitus.

Journal Article↗
PubMed2001

Liver enzyme monitoring in patients treated with troglitazone.

CONTEXT: Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000. OBJECTIVE: To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone. DESIGN, SETTING, AND PARTICIPANTS: Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations. MAIN OUTCOME MEASURES: Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims. RESULTS: Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use. CONCLUSIONS: The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

Chromans↗
PubMed1998

Effect of troglitazone on steady-state pharmacokinetics of digoxin.

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24-hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple-dose troglitazone does not alter the steady-state pharmacokinetics of digoxin.

Administration, Oral↗
PubMed1999

Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes.

AIMS/HYPOTHESIS: Inflammation could play a part in insulin resistance. Thiazolidinediones, new antidiabetic drugs, possess anti-inflammatory effects in vitro. We investigated if acute-phase serum proteins are increased in patients with Type II (non-insulin-dependent) diabetes mellitus who had been treated with insulin and whether troglitazone has anti-inflammatory effects in vivo. METHODS: A total of 27 patients (age 63.0+/-1.7 years, HbA1c 8.8+/-0.3%, BMI 32.7+/-0.8 kg/m2, duration 15.2+/-1.4 years, insulin dose 73.3+/-7.0 U/day) participated in the study. The patients received daily either 400 mg troglitazone or placebo for 16 weeks. Blood samples were taken at baseline, at the end of therapy and after a follow-up time of 23+/-4 days. RESULTS: The concentrations of serum amyloid A (6.2+/-1.1 mg/l) and C-reactive protein (6.1+/-1.1 mg/l) were increased (p < 0.001) and complement protein C3 (1.69+/-0.05 g/l) was also above the reference range for healthy subjects. Placebo treatment had no effect on glucose or inflammation, whereas troglitazone reduced fasting glucose (from 10.4+/-0.6 mmol/l to 8.1+/-0.5 mmol/l, p < 0.01), HbA1c (from 8.7+/-0.3% to 7.5+/-0.3%, p < 0.01), insulin requirements (from 75+/-10 U/day to 63+/-10 U/day, p < 0.05), serum amyloid A (from 6.3+/-1.5 mg/l to 4.0+/-1.3 mg/l, p = 0.001), alpha-1-acid glycoprotein (from 906+/-51 mg/l to 729+/-52 mg/l, p = 0.001) and C3 (from 1.72+/-0.07 g/l to 1.66+/-0.06 g/l, p < 0.05) but not alpha-1-antitrypsin, ceruloplasmin, C-reactive protein or haptoglobin significantly. Concentrations of glucose and acute-phase reactants had returned to those before treatment at the follow-up visit. CONCLUSION/INTERPRETATION: In Type II diabetic patients serum amyloid A and complement protein C3 are raised. Troglitazone exerts a selective reversible action on some acute-phase proteins and C3 but not on others in conjunction with the improvement in glucose metabolism.

Acute-Phase Proteins↗
PubMed2006

Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone.

The effects of rosiglitazone and troglitazone were examined on cloned Kv1.3 channels stably expressed in Chinese hamster ovary cells using the whole-cell configuration of the patch-clamp technique. Rosiglitazone decreased the Kv1.3 currents and accelerated the decay rate of current inactivation in a concentration-dependent manner with an IC(50) of 18.6 microM. These effects were reversible after washout of the drug. Troglitazone caused the block of Kv1.3 with a similar pattern but was five times more potent than rosiglitazone with an IC(50) of 3.5 microM. The block of Kv1.3 by rosiglitazone and troglitazone was voltage-dependent at a membrane potential coinciding with the activation of the channels. Both drugs decreased the tail current amplitude and slowed the deactivation process of Kv1.3, resulting in a tail crossover phenomenon. These results indicate that rosiglitazone and troglitazone block the open state of Kv1.3 channels, suggesting that it is an important pharmacological target for rosiglitazone as a potent blocker of Kv1.3 channels.

Animals↗
PubMed1995

Metabolic effects of troglitazone on fat-induced insulin resistance in the rat.

Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of diet-induced insulin resistance and related abnormalities, we studied its effect on insulin resistance induced by high-fat feeding in rats. Normal male Sprague-Dawley rats were fed a high-fat diet for 3 weeks with and without troglitazone as a food mixture (0.2%) or were fed normal chow. In vivo insulin action was measured using a euglycemic-hyperinsulinemic clamp at two different insulin infusion rates, 4 (submaximal stimulation) and 40 (maximal stimulation) mU/kg/min. Fat feeding markedly reduced the submaximal glucose disposal rate ([GDR], 26.4 +/- 1.3 v 37.5 +/- 1.4 mg/kg/min, P < .01) and maximal GDR (55.9 +/- 1.3 v 64.5 +/- 1.3 mg/kg/min, P < 0.5), reduced the suppressibility of submaximal hepatic glucose production ([HGP], 3.2 +/- 0.9 v 1.5 +/- 0.5 mg/kg/min, P < .05), and resulted in hyperlipidemia. Troglitazone treatment did not affect any of these parameters. Insulin resistance induced by fat feeding is the first experimental model in which troglitazone failed to correct or partially correct the insulin resistance.

Animals↗
PubMed1995

Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives.

The association of hypertension with insulin resistance has been reported. Troglitazone (CS-045) is a newly developed antidiabetic agent that enhances insulin sensitivity. Its antidiabetic effects have been confirmed in diabetic animals and patients. The present study was performed to evaluate whether the amelioration of hyperinsulinemia by troglitazone lowers blood pressure in essential hypertensives. Troglitazone was administered orally to 18 outpatients with essential hypertension complicated by mild diabetes at a dose of 200 mg twice a day for 8 weeks. Blood pressure was decreased from 164 +/- 3/94 +/- 2 mm Hg to 146 +/- 3 (P < .001)/82 +/- 3 (P < .05) mm Hg at 8 weeks of the treatment period. Pulse rate did not change. Fasting plasma glucose changed from 159 +/- 10 mg/dL to 144 +/- 14 mg/dL at 8 weeks (P < .05). Plasma insulin (IRI) levels changes from 9.1 +/- 1.2 microU/mL to 6.3 +/- 0.8 microU/mL at the endpoint of treatment (P < .1). Decrease in mean blood pressure from the control period to the endpoint of the treatment correlated significantly with decrease in IRI (r = 0.59, P < .05). In summary, troglitazone treatment induces improvement in both glucose metabolism and blood pressure control in essential hypertensive patients with diabetes mellitus. These results suggest that insulin resistance or plasma insulin level plays a role in the pathogenesis of essential hypertension.

Aged↗
PubMed2005

Involvement of MEK-ERK signaling pathway in the inhibition of cell growth by troglitazone in human pancreatic cancer cells.

In the present study, we examined a role of mitogen-activated protein kinases (MAPKs), extracellular signal-related kinase (ERK), c-Jun N-terminal protein kinase, and p38 MAPK in troglitazone-induced inhibition of cell growth in human pancreatic cancer cells. Among the three kinases, troglitazone specifically inhibited the phosphorylation of ERK1/2 in a dose- and time-dependent manner. Troglitazone also down-regulated the protein expression of mitogen-activated protein kinase kinase (MEK)1/2, an upstream molecule that regulates ERK phosphorylation. Treatment of human pancreatic cancer cells with specific MEK inhibitor, PD98059 or U0126, inhibited ERK1/2 phosphorylation and cell growth. These results suggest for the first time that the inhibition of the MEK1/2-ERK1/2 signaling pathway may be implicated in the growth inhibitory effect by troglitazone in human pancreatic cancer cells.

Antineoplastic Agents↗
PubMed2005

Troglitazone and 15-deoxy-delta(12,14)-prostaglandin J2 inhibit shear-induced coupling factor 6 release in endothelial cells.

OBJECTIVE: We previously showed that mitochondrial coupling factor 6 (CF6), an endogenous inhibitor of prostacyclin synthesis and a vasoconstrictor, is present on the surface of human umbilical vein endothelial cells (HUVEC) and is released outside of the cells by shear stress. We investigated the intracellular signaling mechanism for shear-induced release of CF6 in HUVEC and the effects of troglitazone and 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2), both peroxisome proliferator-activated receptor (PPAR)-gamma ligands, on it. METHODS AND RESULTS: The release and gene expression of CF6 in HUVEC were enhanced by shear stress at 25 dyn/cm2, measured by radioimmunoassay and real-time RT-PCR, respectively. The intracellular content of CF6 was decreased after exposure to shear stress at 25 dyn/cm2. Transfection experiments with deletional and mutational CF6 promoter constructs, and with dominant negative mutant IkappaB kinase alpha (K44M) demonstrated that shear-induced CF6 transcription was dependent on nuclear factor-kappa B (NF-kappaB) activation. Pretreatment with troglitazone or 15d-PGJ2 inhibited the shear-induced release and gene expression of CF6, whereas fenofibric acid, a PPAR-alpha ligand, had no influence on them. Western blot and immunostaining showed that troglitazone and 15d-PGJ2 inhibited the shear-induced, reactive oxygen species (ROS)-mediated activation of NF-kappaB at the level of IkappaB protein. CONCLUSIONS: The shear-induced gene expression and release of CF6 in HUVEC are mediated by the ROS-related activation of NF-kappaB signaling pathway. Troglitazone and 15d-PGJ2 inhibit them at the IkappaB protein level.

Blotting, Western↗