The nuclear hormone receptor PPARgamma is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARgamma agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 receptor expression, Ang-II-mediated signaling pathways, and Ang-II-induced adrenal aldosterone synthesis/secretion. PPARgamma agonists also inhibit the progression of atherosclerosis in animals and humans, possibly through a pathway involving the suppression of RAAS and the thromboxane A2 system, as well as the protection of endothelial function. Moreover, PPARgamma-agonist-mediated renal protection, especially the reduction of albuminuria, has been observed in diabetic nephropathy, including animal models of the disease, and in non-diabetic renal dysfunction. The renal protective activities may reflect, at least in part, the ability of PPARgamma agonists to lower blood pressure, protect endothelial function, and cause vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPARgamma agonists have recently been described. Based on the multiple therapeutic actions of PPARgamma agonists, they will no doubt lead to novel approaches in the treatment of lifestyle-related and other diseases.
Animals ; Atherosclerosis/prevention & control ; Humans ; Hypertension/drug therapy ; Hypoglycemic Agents/*pharmacology ; Kidney Diseases/etiology ; PPAR gamma/*agonists ; PPAR-beta/agonists

OBJECTIVETo explore the changes on the content of substrate, the activity of correlative enzyme and the mRNA and protein expressions of beta(3)-adrenoceptor and peroxisome proliferator-activated receptor alpha (PPARalpha) in human failing heart.

METHODPapillary muscles from 20 patients with heart failure during mitral valves replacement and 6 control subjects died of non-cardiac accidents were obtained and free fat acid (FFA), lactic acid (LD) and the activity of Na(+)K(+)-ATPase and Ca(2+)Mg(2+)-ATPase, protein and mRNA expressions of beta(3)-adrenergic receptor and PPARalpha were measured.

RESULTIn the failing heart, the contents of fat acid, LD and expression of beta(3)-adrenoceptor mRNA and protein were significantly higher while the activity of Na(+)K(+)-ATPase and Ca(2+)Mg(2+)-ATPase, expressions of PPARalpha at mRNA and protein levels were significantly lower than those in control myocardium.

CONCLUSIONMetabolic remodeling (upregulation of beta(3)-adrenoceptor and downregulation of PPARalpha) might contribute to the pathophysiology of heart failure.

Adult ; Female ; Heart Failure ; metabolism ; Humans ; Male ; Middle Aged ; Myocardium ; metabolism ; PPAR alpha ; metabolism ; Receptors, Adrenergic, beta-3 ; metabolism

BACKGROUNDS/AIMS: During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. METHODS: Peroxisome proliferator-activated receptors (PPARs: PPARalpha, beta/delta, and gamma) regulate fatty acid metabolism, glucose homeostasis, cell proliferation, differentiation and inflammation. Proinflammatory profiles including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are the important pathological factors in inflammatory responses during the pathological progression of the acute phase response. Lipopolysaccarides (LPS) induced the expression of TNF-alpha, IL-1beta, and IL-6. LPS-induced inflammation decrease the expression of peroxisome proliferator-activated receptor alpha (PPARalpha), PPARbeta/delta, PPARgamma, and coactivators PPARgamma co-activator 1 alpha (PGC-1alpha), PGC-1beta messenger RNA (mRNA) in the liver of Balb/c mouse. In addition, LPS-induced inflammation diminishes the protein level of PPARalpha, PPARbeta/delta, and PPARgamma. Proinflammatory cytokines including TNFalpha, IL-1beta, and IL-6 are the principal reducer of PPARs. However, the knockout mouse model against TNFalpha and IL-6 does not block decrease of PPARs in serum and liver. The mice were pretreated with fenofibrate at 100 mg/kg for 2 days. RESULTS: These treatment protocols increased the amount of PPARs mRNA in the liver. Fenofibrate inhibited LPS-induced TNF-alpha, IL-1beta, and IL-6 production in the serum and liver. Similar results were obtained when human hepatoma HepG2 cells exposed to LPS were co-incubated with fenofibrate. LPS-treated HepG2 cells decreased expression of IkappaB. Moreover, activation of PPARs abrogated LPS-induced degradation of IkappaB, thus suppressing LPS-induced NF-kappaB activities. CONCLUSIONS: Therefore, fenofibrate decreases the expression and secretion of TNF-alpha, IL-1beta, and IL-6 via the NF-kappaB signaling pathway, thus serving as therapeutic targets to attenuate inflammation that is involved in hepatic pathological progression.
Animals ; Bile ; Carcinoma, Hepatocellular ; Cell Proliferation ; Clinical Protocols ; Cytokines ; Fenofibrate ; Glucose ; Hep G2 Cells ; Homeostasis ; Humans ; Inflammation ; Interleukin-1beta ; Interleukin-6 ; Lipid Metabolism ; Lipoproteins ; Liver ; Mice ; Mice, Knockout ; NF-kappa B ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes ; PPAR alpha ; PPAR-beta ; PPAR delta ; PPAR gamma ; RNA, Messenger ; Tumor Necrosis Factor-alpha

OBJECTIVETo explore the effect of atorvastatin on cardiac hypertrophy and to determine the potential mechanism involved.

METHODSAn in vitro cardiomyocyte hypertrophy from neonatal rats was induced with angiotensin II (Ang II) stimulation. Before Ang II stimulation, the cultured rat cardiac myocytes were pretreated with atorvastatin at different concentrations (0.1, 1, and 10 μmol/L). The following parameters were evaluated: the myocyte surface area, 3H-leucine incorporation into myocytes, mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase 9, matrix metalloproteinase 2, and interleukin-1β, mRNA and protein expressions of the δ/β peroxisome proliferator-activated receptor (PPAR) subtypes.

RESULTSIt was shown that atorvastatin could ameliorate Ang II-induced neonatal cardiomyocyte hypertrophy in the area of cardiomyocytes, 3H-leucine incorporation, and the expression of atrial natriuretic peptide and brain natriuretic peptide markedly. Meanwhile, atorvastatin also inhibited the augmented mRNA level of several cytokines in hypertrophic myocytes. Furthermore, the down-regulated expression of PPAR- δ/β at both the mRNA and protein levels in hypertrophic myocytes could be significantly reversed by atorvastatin treatment.

CONCLUSIONSAtorvastatin could improve Ang II-induced cardiac hypertrophy and inhibit the expression of cytokines. Such effect might be partly achieved through activation of the PPAR-δ/β pathway.

Angiotensin II ; pharmacology ; Animals ; Atorvastatin Calcium ; pharmacology ; therapeutic use ; Cardiomegaly ; metabolism ; pathology ; prevention & control ; Cells, Cultured ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; PPAR delta ; genetics ; PPAR-beta ; genetics ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effects of atorvastatin on angiotensin II (Ang II)-induced hypertrophy of cardiac myocytes (MC) and the changes of mRNA expression of peroxisome proliferators-activated receptor alpha, gamma (PPAR alpha, gamma) subtypes in vitro.

METHODSHypertrophy in neonatal rat MC was established with Ang II and treated with atorvastatin. The surface area of MC was analyzed by the aid of NIH Image J software, and the synthetic rate of protein in MC was detected by (3)H-leucine incorporation. mRNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), matrix metalloproteinase (MMP) 9, MMP2, interleukin1beta (IL-1beta) and PPARalpha, gamma was measured by reverse transcription-polymerase chain reaction (RT-PCR).

RESULTSChanges of MC were detected induced by Ang II, including increases in surface area, mRNA expression of ANP, BNP, MMP9, MMP2 and IL-1beta, and (3)H-leucine incorporation, as well as a decrease in mRNA expression of PPARalpha, gamma. Treatment with atorvastatin inhibited the changes above in a dose-dependent manner, but no change was found in treated with DMSO.

CONCLUSIONAtorvastatin inhibits cardiac hypertrophy in vitro. It is suggested that atorvastatin has a potential role in the prevention and treatment of cardiac diseases such as cardiac hypertrophy, and PPAR alpha and gamma maybe involved in this process.

Angiotensin II ; Animals ; Atorvastatin Calcium ; Cardiomegaly ; metabolism ; Cells, Cultured ; Gene Expression Regulation ; Heptanoic Acids ; pharmacology ; Myocytes, Cardiac ; drug effects ; metabolism ; PPAR alpha ; metabolism ; PPAR-beta ; metabolism ; Pyrroles ; pharmacology ; Rats ; Rats, Wistar ; Up-Regulation

BACKGROUNDAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the first steps in the development of multiple organ failure induced by sepsis. A systemic excessive inflammatory reaction is currently the accepted mechanism of the pathogenesis of sepsis. Several studies have suggested a protective role of the peroxisome proliferator activated receptor-β/δ (PPAR-β/δ) in related inflammatory diseases. But the role of PPARβ/δ in ALI remains uncertain. The aim of this study was to investigate the role and possible mechanism of PPARβ/δ in ALI induced by sepsis.

METHODSCecal ligation and puncture (CLP) was used as a sepsis model. Rats were randomly divided into four groups, the control group (CON, n = 6), sham-operation group (SHAM, n = 12), cecal ligation and puncture group (CLP, n = 30), GW501516 group (CLP+GW, n = 25), which underwent CLP and were subcutaneously injected with the PPAR-β/δ agonist GW501516 (0.05 mg/100 g body weight). Survival was monitored to 24 hours after operation. Blood pressure, serum creatinine, blood urea nitrogen, aspartate aminotrasferase and alanine aminotrasferase were measured after CLP. Concentrations of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β in serum were detected by enzyme linked immunosorbent assay (ELISA) kits. Lung tissue samples were stained with H&E and scored according to the degree of inflammation. Bacterial colonies were counted in the peritoneal fluid. Alveolar macrophages were cultured and incubated with GW501516 (0.15 µmol/L) and PPARβ/δ adenovirus and then treated with Lipopolysaccharide (2 µg/ml) for 2 hours. The TNF-α, IL-1β and IL-6 RNA in lung and alveolar macrophages were determined by real-time PCR. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in lung and alveolar macrophages was detected by Western blotting.

RESULTSGW501516 significantly increased the survival of septic rats, decreased histological damage of the lungs, reduced inflammatory cytokines in serum and lung tissues of septic rats and did not increase counts of peritoneal bacteria. In vitro, GW501516 and over-expression of PPARβ/δ attenuated gene expression of TNF-α, IL-1β and IL-6 in alveolar macrophages. Both in vivo and in vitro, PPARβ/δ inhibited the phosphorylation of STAT3.

CONCLUSIONPPARβ/δ plays a protective role in sepsis induced ALI via suppressing excessive inflammation.

Acute Lung Injury ; drug therapy ; etiology ; Animals ; Cells, Cultured ; Male ; PPAR delta ; agonists ; metabolism ; PPAR-beta ; agonists ; metabolism ; Rats ; Rats, Sprague-Dawley ; Sepsis ; complications ; drug therapy ; Thiazoles ; therapeutic use

OBJECTIVETo explore the role of EGF in regulating HaCaT apoptosis through peroxisome proliferator-activated receptor beta (PPARbeta).

METHODSCultured HaCaT cells were divided into different groups with different additives in culture medium as control (normal culture), TNF-alpha (with addition of 10 ng/mL TNF-alpha), EGF (with addition of 20 ng/mL EGF), EGF + TNF-alpha (cells were treated with 10 ng/mL TNF-alpha for 60 mins after the exposure to 20 ng/mL EGF for 4 hs) groups. Conjugation activity and transcription activity of PPARbeta of HaCaT cells in each group were detected by electrophoretic mobility shift assay (EMSA) and luciferase gene analysis (LGA). Protein expression of PPARbeta of HaCaT cells after transfected by missense oligonucleotide (scrODN) and antisense oligonucleotide (asODN) was determined by Western blot. Caspase-3 activity and apoptosis rate were detected by flow cytometry.

RESULTSConjugation and transcription activity of PPARbeta DNA were enhanced as shown in EMSA and LGA. Compared with that of cells in groups transfected by scrODN, protein expression of PPARbeta in cells of groups transfected by asODN was obviously inhibited as shown in Western blot. Caspase-3 activity of cells in TNF-alpha and EGF + TNF-alpha groups transfected by asODN was stronger than that of cells in TNF-alpha and EGF + TNF-alpha groups transfected by scrODN (P < 0.01). Apoptosis rate of cells in control, EGF, TNF-alpha, and EGF + TNF-alpha groups which were transfected by scrODN was (7.31 +/- 0.45)%, (7.43 +/- 0.21)%, (39.78 +/- 0.65)%, (28.34 +/- 0.54)% respectively, and that in those groups transfected by asODN was (8.22 +/- 0.51)%, (7.83 +/- 0.67)%, (46.78 +/- 0.48)%, (44.69 +/- 0.83)%. Apoptosis rate of cells in TNF-alpha and EGF + TNF-alpha groups transfected by asODN was respectively higher than that in TNF-alpha and EGF + TNF-alpha groups transfected by scrODN (P < 0.01).

CONCLUSIONSEGF inhibits HaCaT KC apoptosis caused by TNF-alpha in a PPARbeta-dependent manner.

Apoptosis ; drug effects ; Cell Culture Techniques ; Cell Line ; Epidermal Growth Factor ; pharmacology ; Humans ; PPAR-beta ; genetics ; metabolism ; Transcription, Genetic ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors

OBJECTIVETo study the effect of freeze-dried mouse epidermal growth factor (mEGF) on the expression of peroxisome proliferator-activated receptor &beta; (PPAR-&beta;) in mice during wound healing.

METHODSFull-thickness skin defect with area of 1.5 cm × 1.5 cm was reproduced on both sides of the back of 70 BALB/c mice (2 wounds in each mouse). The wound on the left side in each mouse was treated with 5 µg/mL mEGF solution (experiment group), and that on the right side in each mouse was treated with saline (control group). On post injury day (PID) 7, 11, and 16, 20 mice were used for determination of wound healing rate at each time point. On PID 1, 3, 7, 11, 14, and 18, specimens of wound edge were harvested for determination of protein and gene expression of PPAR-&beta; with immunohistochemical staining and in situ hybridization, with 10 specimens at each time point (denoted as integral absorbance value). Data were processed with t test.

RESULTS(1) Wound healing rate. The wound healing rate in experiment group on PID 7, 11, and 16 was respectively higher than that in control group (with t value respectively 3.03, 6.05, 11.9, P values all below 0.01). (2) Immunohistochemical observation. In both groups, the PPAR-&beta; proteins highly expressed in fibroblasts of wound granulation tissues and nuclei of keratinocytes located in wound edge at early stage after injury, and they highly expressed in newly formed epidermis and their fibroblasts in the lower layer after wound epithelization. The expression of PPAR-&beta; protein was gradually decreased after wound healing. The expression of PPAR-&beta; protein at each time point in experiment group was respectively higher than that in control group (with t values from 2.15 to 7.37, P < 0.05 or P < 0.01). The expression of PPAR-&beta; protein peaked on PID 3 in experiment group [(3.46 ± 1.33) × 10(3)], which was (2.35 ± 1.09) × 10(3) in control group. (3) In situ hybridization. The expression levels of PPAR-&beta; mRNA in both groups were up-regulated after injury, which were mainly observed in fibroblasts of wound and cytoplasm of KC in wound edge, but they were down-regulated after wound epithelization. The expression of PPAR-&beta; mRNA at each time point in experiment group was respectively higher than that in control group (with t values from 2.35 to 6.64, P < 0.05 or P < 0.01). The expression of PPAR-&beta; mRNA in both groups peaked on PID 3 [(7.3 ± 2.6) × 10(6), (4.5 ± 3.0) × 10(6), respectively].

CONCLUSIONSmEGF can up-regulate the expression of PPAR-&beta; in wound tissue of mice and promote wound healing.

Animals ; Epidermal Growth Factor ; pharmacology ; Female ; Granulation Tissue ; metabolism ; Male ; Mice ; Mice, Inbred BALB C ; PPAR-beta ; metabolism ; Skin ; injuries ; metabolism ; Wound Healing ; drug effects

OBJECTIVETo study the effect of beta3 adrenergic receptor (beta3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2 (PPARgamma2) Prol2Ala polymorphisms on insulin resistance.

METHODSOne hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment (HOMA). PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state (IBS) was used to analyze the association of polymorphisms with insulin sensitivity.

RESULTSThe genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Prol2Pro, Prol2Ala, and Alal2Ala were 89.9%, 9.6%, and 0.5%, respectively. For beta3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio (WHR), blood glucose (GLU), and insulin (INS), homeostasis model assessment insulin resistance index (HOMA-IR) of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA-IR had statistic significance. For PPARgamma2 Pro12Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index (BMI), WHR, percent of body fat (PBF) and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS.

CONCLUSIONSBeta3AR Trp64Arg and PPARgamma2 Pro12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.

Adolescent ; Child ; Child, Preschool ; Genotype ; Humans ; Insulin Resistance ; genetics ; Obesity ; genetics ; PPAR gamma ; genetics ; Polymorphism, Genetic ; Receptors, Adrenergic, beta-3 ; genetics ; Twins, Dizygotic ; genetics ; metabolism

OBJECTIVETo explore the effect of curcumin on TGF-&beta;2 regulated peroxisome proliferater activated receptor y (PPAR-γ)/platelet derived growth factor &beta; (PDGF-&beta;) signaling pathway in lung fibroblasts of mice.

METHODSC57BL/6 mouse lung fibroblasts were in vitro cultured with TGF-&beta;2, curcumin, or TGF-&beta;2 plus curcumin. The cell proliferation was detected by cell growth counting in the blank control group, low, middle, and high dose curcumin groups (5, 25, 50 μmol/L), the TGF-&beta;2 (10 ng/mL) group, TGF-&beta;2 (10 ng/mL) plus curcumin (5, 25, 50 μmol/L) groups. mRNA expressions of PPAR-γ, platelet-derived growth factor receptor &beta; (PDGFR-&beta;), fibroblast growth factor R1 (FGFR1) were detected using reverse transcription PCR. Protein levels of PPAR-γ and collagen-1 were detected using Western blot and ELISA in the blank control group, the TGF-&beta;2 group, the TGF-&beta;2 (10 ng/mL) plus curcumin 50 μmol/L group.

RESULTSCompared with the blank control group, curcumin 50 μmol/L showed the most significant inhibition on cell proliferation at 48 h and 72 h. Compared with the TGF-&beta;2 group, TGF-&beta;2 (10 ng/mL) plus curcumin 50 mol/L also showed the most significant inhibition on cell proliferation at 48 h and 72 h. Compared with the blank control group, mRNA expressions of PPAR-γ and PDGF-&beta;, as well as protein expression of PPAR-γ increased, the collagen-1 expression also increased in the TGF-&beta;2 group (P < 0.05). Compared with the TGF-&beta;2 group, mRNA expressions of PPAR-γ obviously increased in the TGF-&beta;2 (10 ng/mL) plus curcumin 25 μmol/L group and the TGF-&beta;2 (10 ng/mL) plus curcumin 50 μmol/L group, higher than that in the TGF-&beta;2 (10 ng/mL) plus curcumin 5 [μmol/L group (P < 0.05). mRNA expressions of PPAR-γ was higher in the TGF-&beta;2 (10 ng/mL) plus curcumin 50 μmol/L group than in the TGF-&beta;2 (10 ng/mL) plus curcumin 25 μmol/L group (P < 0.05). mRNA expressions of PDGF-&beta; was lower in TGF-&beta;2 (10 ng/mL) plus curcumin groups than in the TGF-&beta;2 group (P < 0.05). Besides, PDGF-&beta; mRNA expressions were lower in the TGF-&beta;2 (10 ng/mL) plus curcumin 50 μmol/L group than in the TGF-&beta;2 (10 ng/mL) plus curcumin 5 μmol/L group and the TGF-&beta;2 (10 ng/mL) plus curcumin 25 μmol/L group (P < 0.05). There was no statistical difference in FGFR1 mRNA expressions between the TGF-&beta;2 group and 3 TGF-&beta;2 plus curcumin groups (P > 0.05). Compared with the TGF-&beta;2 group, PPAR-γ protein expressions increased and collagen-1 protein expressions decreased in the TGF-&beta;2 (10 ng/mL) plus curcumin 50 μLmol/L group (P < 0.05, P < 0.01).

CONCLUSIONSCurcumin not only could inhibit TGF-&beta;2 induced proliferation of lung fibroblasts, but also could inhibit the synthesis of collagens. These might be associated with up-regulating PPAR-γ expressions and down-regulating PDGF-&beta; expressions. Therefore, curcumin might inhibit the occurrence and developing of lung fibrosis through blocking PPAR-γ/PDGF-&beta; signaling pathway.

Animals ; Cell Proliferation ; Collagen ; Curcumin ; pharmacology ; Fibroblasts ; metabolism ; Lung ; drug effects ; metabolism ; Mice ; Mice, Inbred C57BL ; PPAR gamma ; metabolism ; RNA, Messenger ; Receptor, Platelet-Derived Growth Factor beta ; metabolism ; Signal Transduction ; Transforming Growth Factor beta ; Transforming Growth Factor beta2 ; metabolism