Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes

2011 ◽  
Vol 121 (7) ◽  
pp. 305-312 ◽  
Author(s):  
Ting-I Lee ◽  
Yu-Hsun Kao ◽  
Yao-Chang Chen ◽  
Nan-Hung Pan ◽  
Yung-Kuo Lin ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Heart Function ◽  
Receptor Expression ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Spontaneously Hypertensive ◽  
Protein Levels ◽  
Ppar Γ ◽  
Tnf Α ◽  
Wistar Kyoto

Hypertension and DM (diabetes mellitus) are common chronic disorders that often co-exist. DM and PPAR (peroxisome-proliferator-activated receptor)-γ agonists may directly impair heart function. However, the effects of DM and PPAR-γ agonists on hypertensive myocardium are not known. Hence the aim of the present study was to investigate whether DM and a PPAR-γ agonist [RGZ (rosiglitazone)] modulated the effects of hypertension on myocardial expression of PPAR isoforms. Cardiac PPAR isoforms, TNF (tumour necrosis factor)-α and IL (interleukin)-6 were evaluated by real-time PCR and Western blotting in SHRs (spontaneously hypertensive rats), diabetic SHRs, diabetic SHRs treated with RGZ (5 mg/kg of body weight) and control WKY (Wistar–Kyoto) rats. Cardiac NADPH oxidase activity was quantified using a SOD (superoxide dismutase)-sensitive cytochrome c reduction assay. When compared with hearts from control WKY rats, hearts from SHRs had decreased PPAR-α and PPAR-δ mRNA and protein levels (39 and 44% respectively for PPAR-α, and 37 and 42% respectively for PPAR-δ), but had increased PPAR-γ mRNA and protein levels (1.9- and 1.4-fold respectively). The hypertension-induced changes in mRNA and protein of cardiac PPAR isoforms were enhanced in diabetic SHRs, which were attenuated in diabetic SHRs treated with RGZ. Cardiac TNF-α and IL-6 protein levels and NADPH oxidase activities were increased in SHRs and were increased further in diabetic SHRs. RGZ treatment decreased TNF-α and IL-6 protein levels and NADPH oxidase activities in hearts from diabetic SHRs. In conclusion, these findings suggest that DM and the PPAR-γ agonist modulated the hypertensive effects on cardiac PPAR isoform expression.

Endotoxin downregulates peroxisome proliferator-activated receptor-γ via the increase in TNF-α release

2008 ◽  
Vol 294 (1) ◽  
pp. R84-R92 ◽  
Author(s):  
Mian Zhou ◽  
Rongqian Wu ◽  
Weifeng Dong ◽  
Asha Jacob ◽  
Ping Wang
Keyword(s):  
Gene Expression ◽  
Neutralizing Antibodies ◽  
Cecal Ligation ◽  
Polymyxin B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Ppar Γ ◽  
Tnf Α ◽  
A Cell

The nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is anti-inflammatory in a cell-based system and in animal models of endotoxemia. We have shown that PPAR-γ gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR-γ is altered in sepsis and, if so, whether LPS directly downregulates PPAR-γ. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10, and 20 h after CLP. PPAR-γ gene expression and protein levels were determined by RT-PCR and Western blot analysis, respectively. The results showed that PPAR-γ gene expression decreased at 10 and 20 h and that its proteins levels were reduced at 20 h after CLP. PPAR-γ levels were also decreased in animals that were administered LPS. To determine the direct effects of LPS on PPAR-γ downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. The administration of PMB significantly reduced plasma levels of endotoxin, but it did not prevent the downregulation of PPAR-γ expression. We found that circulating levels of TNF-α still remained significantly elevated in PMB-treated septic animals. We, therefore, hypothesize that the decrease of PPAR-γ expression is TNF-α dependent. To investigate this, Kupffer cells (KCs) were isolated from normal rats and stimulated with LPS or TNF-α. TNF-α significantly attenuated PPAR-γ gene expression in KCs. Although LPS decreased PPAR-γ in KCs, the downregulatory effect of LPS was blocked by the addition of TNF-α-neutralizing antibodies. Furthermore, the administration of TNF-α-neutralizing antibodies to animals before the onset of sepsis prevented the downregulation of PPAR-γ in sepsis. We, therefore, conclude that LPS downregulates PPAR-γ expression during sepsis via an increase in TNF-α release.

Gabapentin Reduces Alcohol Intake in Rats by Regulating NF-κB Signaling Pathway Via PPAR γ

2021 ◽  
Author(s):  
Jing Li ◽  
Kewei Xu ◽  
Hao Ding ◽  
Qiaozhen Xi
Keyword(s):  
Locomotor Activity ◽  
Signaling Pathway ◽  
Specific Inhibitor ◽  
Underlying Mechanism ◽  
Ethanol Consumption ◽  
Diglycidyl Ether ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α

Abstract Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

15 Deoxy Δ12,14 PGJ2 Induces Procoagulant Activity in Cultured Human Endothelial Cells

2002 ◽  
Vol 87 (03) ◽  
pp. 523-529 ◽  
Author(s):  
Shaoping Xie ◽  
David O’Regan ◽  
Vijay Kakkar ◽  
Michael Scully
Keyword(s):  
Endothelial Cells ◽  
Peroxisome Proliferator ◽  
Endothelial Protein C Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligand ◽  
Ppar Γ ◽  
Tnf Α ◽  
Ea.Hy926 Cells ◽  
High Affinity Ligand ◽  
Feedback Regulator

Summary15 deoxy Δ12,14 PGJ2 (15d-PGJ2), a high affinity ligand of peroxisome proliferator-activated receptor γ (PPAR γ has been proposed to act as a negative feedback regulator of the inflammatory response. We investigated the effect of 15d-PGJ2 on the anticoagulant property of endothelial cells. 15d-PGJ2 stimulated a moderate but sustained increase in tissue factor (TF) activity in HUVECs and EA.hy926 cells while causing a partial loss of thrombomodulin (TM) activity. When cells were co-treated with 15d-PGJ2 and TNF-α, the subsequent elevation of TF activity was synergistically increased over that of cells treated with TNF-α, alone and the decline of TF activity after 24 h was less marked than TNF-α, alone. The induction of TF by 15d-PGJ2 alone and in combination with TNF-α, was reduced in the presence of PD 98059, suggesting the participation of the MEK/ERK pathway. The thiazolidinedione PPAR γ agonist ciglitazone had no effect on TF levels but reduced the expression of endothelial protein C receptor. The ability of 15d-PGJ2 to enhance a procoagulant phenotype arising from TNF-α, suggests a pro-inflammatory role for the prostaglandin.

Agouti regulates adipocyte transcription factors

2001 ◽  
Vol 280 (4) ◽  
pp. C954-C961 ◽  
Author(s):  
Randall L. Mynatt ◽  
Jacqueline M. Stephens
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Paracrine Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Skeletal Mass ◽  
Ppar Γ ◽  
Obesity And Diabetes

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agoutiexpression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-γ protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-γ.

PPAR-γ ligands modulate effects of LPS in stimulated rat synovial fibroblasts

2002 ◽  
Vol 282 (1) ◽  
pp. C125-C133 ◽  
Author(s):  
Marie-Agnès Simonin ◽  
Karim Bordji ◽  
Sandrine Boyault ◽  
Arnaud Bianchi ◽  
Elvire Gouze ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Constitutive Expression ◽  
Synovial Fibroblasts ◽  
Binding Activity ◽  
Inos Mrna ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Cox 2

This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-α in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-γ expression induced by 10 μg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-α mRNA expression was not modified. 15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (−80%) and inducible nitric oxide synthase (iNOS) mRNA expression (−80%), whereas troglitazone (10 μM) only inhibited iNOS mRNA expression (−50%). 15d-PGJ2 decreased LPS-induced interleukin (IL)-1β (−25%) and tumor necrosis factor (TNF)-α (−40%) expression. Interestingly, troglitazone strongly decreased TNF-α expression (−50%) but had no significant effect on IL-1β expression. 15d-PGJ2 was able to inhibit DNA-binding activity of both nuclear factor (NF)-κB and AP-1. Troglitazone had no effect on NF-κB activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ2 and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-α and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-γ ligands and underline different mechanisms of action of 15d-PGJ2 and troglitazone in synovial fibroblasts.

Peroxisome proliferator-activated receptor-γ ligands regulate endothelial membrane superoxide production

2005 ◽  
Vol 288 (4) ◽  
pp. C899-C905 ◽  
Author(s):  
Jinah Hwang ◽  
Dean J. Kleinhenz ◽  
Bernard Lassègue ◽  
Kathy K. Griendling ◽  
Sergey Dikalov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Molecular Mechanisms ◽  
Pcr Analysis ◽  
Resonance Spectroscopy ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Endothelial Nitric Oxide

Recently, we demonstrated that the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, either 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, increased endothelial nitric oxide (·NO) release without altering endothelial nitric oxide synthase (eNOS) expression ( 4 ). However, the precise molecular mechanisms of PPAR-γ-stimulated endothelial·NO release remain to be defined. Superoxide anion radical (O2−·) combines with ·NO to decrease·NO bioavailability. NADPH oxidase, which produces O2−·, and Cu/Zn-superoxide dismutase (Cu/Zn-SOD), which degrades O2−·, thereby contribute to regulation of endothelial cell·NO metabolism. Therefore, we examined the ability of PPAR-γ ligands to modulate endothelial O2−· metabolism through alterations in the expression and activity of NADPH oxidase or Cu/Zn-SOD. Treatment with 10 μM 15d-PGJ2 or ciglitazone for 24 h decreased human umbilical vein endothelial cell (HUVEC) membrane NADPH-dependent O2−· production detected with electron spin resonance spectroscopy. Treatment with 15d-PGJ2 or ciglitazone also reduced relative mRNA levels of the NADPH oxidase subunits, nox-1, gp91 phox (nox-2), and nox-4, as measured using real-time PCR analysis. Concordantly, Western blot analysis demonstrated that 15d-PGJ2 or ciglitazone decreased nox-2 and nox-4 protein expression. PPAR-γ ligands also stimulated both activity and expression of Cu/Zn-SOD in HUVEC. These data suggest that in addition to any direct effects on endothelial·NO production, PPAR-γ ligands enhance endothelial·NO bioavailability, in part by altering endothelial O2−· metabolism through suppression of NADPH oxidase and induction of Cu/Zn-SOD. These findings further elucidate the molecular mechanisms by which PPAR-γ ligands directly alter vascular endothelial function.

scholarly journals MAR1 suppresses inflammatory response in LPS-induced RAW 264.7 macrophages and human primary peripheral blood mononuclear cells via the SIRT1/PGC-1α/PPAR-γ pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei Wang ◽  
Rong-Li Xu ◽  
Ping He ◽  
Rui Chen
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
Raw 264.7 ◽  
Peroxisome Proliferator ◽  
Peripheral Blood Mononuclear ◽  
Peroxisome Proliferator Activated Receptor ◽  
Raw 264.7 Macrophages ◽  
Ppar Γ ◽  
Tnf Α ◽  
Blood Mononuclear Cells

Abstract Background Sepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified. Methods RAW 264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs) were pretreated with LPS and MAR1. The mRNA expression and supernatant levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by RT-qPCR and ELISA, respectively. The expression levels of Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were determined by RT-qPCR and Western blot analysis, respectively. Results Our results show that LPS-induced inflammation increased the expression and secretion of proinflammatory cytokines TNF-α, IL-1β and IL-6 and induced suppression of SIRT1, PGC-1α, and PPAR-γ expression, which could be reversed by MAR1. And the effect of MAR1 was eliminated by repression of SIRT1/PPAR-γ and enhanced by PGC-1α overexpression. Conclusions MAR1 suppressed inflammatory response in LPS-induced RAW 264.7 macrophages and hPBMCs via the SIRT1/PGC-1α/PPAR-γ pathway.

Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

2007 ◽  
Vol 293 (1) ◽  
pp. E219-E227 ◽  
Author(s):  
Wei Liao ◽  
M. T. Audrey Nguyen ◽  
Takeshi Yoshizaki ◽  
Svetlana Favelyukis ◽  
David Patsouris ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Interfering Rna

Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interfering RNA (siRNA) sequences and used lentiviral short hairpin RNA and electroporation of siRNAs to deplete PPAR-γ from 3T3-L1 adipocytes to elucidate its role in adipogenesis and insulin signaling. We show that PPAR-γ knockdown prevented adipocyte differentiation but was not required for maintenance of the adipocyte differentiation state after the cells had undergone adipogenesis. We further demonstrate that PPAR-γ suppression reduced insulin-stimulated glucose uptake without affecting the early insulin signaling steps in the adipocytes. Using dual siRNA strategies, we show that this effect of PPAR-γ deletion was mediated by both GLUT4 and GLUT1. Interestingly, PPAR-γ-depleted cells displayed enhanced inflammatory responses to TNF-α stimulation, consistent with a chronic anti-inflammatory effect of endogenous PPAR-γ. In summary, 1) PPAR-γ is essential for the process of adipocyte differentiation but is less necessary for maintenance of the differentiated state, 2) PPAR-γ supports normal insulin-stimulated glucose transport, and 3) endogenous PPAR-γ may play a role in suppression of the inflammatory pathway in 3T3-L1 cells.

scholarly journals Exogenous adiponectin with full Peroxisome proliferator-activated receptor agonists (pioglitazone) abrogates streptozotocin induced oxidative stress and vascular abnormalities in Spontaneously hypertensive rats.

2020 ◽  
Author(s):  
Sheryar Afzal ◽  
Munavvar Abdul Sattar ◽  
Edward James Johns ◽  
Olorunfemi. A. Eseyin
Keyword(s):  
Oxidative Stress ◽  
Arterial Stiffness ◽  
Peroxisome Proliferator ◽  
Oxygen Species ◽  
Adiponectin Concentration ◽  
Peroxisome Proliferator Activated Receptor ◽  
Spontaneously Hypertensive ◽  
Plasma Adiponectin ◽  
Ppar Γ ◽  
Lipid Contents

Abstract Background Oxidative stress, associates with metabolic and anthropometric perturbations, leads to reactive oxygen species production and decrease in plasma adiponectin concentration. We investigated pharmacodynamically the pathophysiological role and potential implication of exogenously administered adiponectin with full and partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists on modulation of oxidative stress, metabolic dysregulation and antioxidant potential in streptozotocin induced Spontaneously hypertensive rats (SHR).Methods Group I (WKY) serve as normotensive control, whereas 42 male SHRs were randomized equally into 7 groups (n = 6), group II: SHR control, groups III: SHR diabetic control, group IV, V and VI treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg) and adiponectin (2.5 µg/kg), whereas, groups VII and VIII received co-treatments as irbesartan + adiponectin), (pioglitazone + adiponectin) respectively. Diabetes was induced using an intra-peritoneal injection of Streptozotocin (40 mg/kg). Plasma adiponectin, lipid contents, arterial stiffness with oxidative stress bio-markers were measured using an in-vitro and in-vivo analysis.Results Diabetic SHRs exhibited hyperglycaemia, hypertriglyceridemia, hypercholesterolemia, increased arterial stiffness with reduced plasma adiponectin and antioxidant enzymatic levels (P < 0.05). Diabetic SHRs pre-treated with pioglitazone and adiponectin separately exerted improvements in antioxidant enzyme activities, abrogated arterial stiffness, offset the increased production of reactive oxygen species and dyslipidaemic effects of STZ, except for blood pressure values which were more pronounced with irbesartan treated groups (all P < 0.05).Conclusions The combined treatment of exogenously administered adiponectin with full PPAR-γ agonist augmented the improvement in lipid contents and adiponectin concentration, restores arterial stiffness with antioxidant potential effects, indicating degree of synergism between adiponectin and full PPAR-γ agonists (pioglitazone).

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