scholarly journals Telmisartan-induced eNOS gene expression is partially independent of its PPAR-gamma agonist property

2012 ◽  
Vol 35 (2) ◽  
pp. 55 ◽  
Author(s):  
Nisa Buset Ríos ◽  
Francisco Rodríguez Esparragón ◽  
José C Rodríguez Pérez
Keyword(s):  
Gene Expression ◽  
Protein Level ◽  
Ppar Gamma ◽  
Enos Gene ◽  
Angiotensin Ii Receptor Blocker ◽  
Peroxisome Proliferator ◽  
Angiotensin Ii Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enos Activity ◽  
Ppar Γ

Purpose: Telmisartan, an angiotensin II receptor blocker (ARB), also acts as an activator of peroxisome proliferator-activated receptor-gamma (PPAR-gamma; PPAR-γ). Several studies have explored the PPAR-γ-endothelial nitric oxide synthase (eNOS) pathway associated with improvement of endothelial function by telmisartan. The ability of telmisartan to induce gene expression and protein level of eNOS and PPARγ in adipocytes was investigated. Methods: Expression of aP2, PPARγ, eNOS and iNOS genes were measured using the quantitative real-time polymerase chain reaction. The changes, at the protein level, were explored by Western blot, which evaluated the native and phosphorylated eNOS forms, eNOS-Ser1177 and eNOS-Thr495. Results: Adipocytes, exposed to telmisartan, exhibited an increase in PPARγ gene expression but a decrease in protein level. Nonetheless, after the exposure to telmisartan, eNOS-Ser1177 phosphorylation, associated with eNOS activity increment, reached its highest value while eNOS-Thr495 phosphorylation, involved in the inhibition of eNOS activity, showed its lowest value. Conclusion: The results suggest that telmisartan preserves eNOS activity via a mechanism that is partially independent of the PPARγ-eNOS pathway in adipocytes.

scholarly journals Telmisartan Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

2020 ◽  
Vol 25 (6) ◽  
pp. 297-308
Author(s):  
Maurizio Cortada ◽  
Eric Wei ◽  
Neha Jain ◽  
Soledad Levano ◽  
Daniel Bodmer
Keyword(s):  
Hair Cells ◽  
Cell Types ◽  
Protective Role ◽  
Angiotensin Ii Receptor Blocker ◽  
Peroxisome Proliferator ◽  
Angiotensin Ii Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Auditory Hair Cells ◽  
Ppar Γ

<b><i>Background:</i></b> Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. <b><i>Objectives:</i></b> The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. <b><i>Methods:</i></b> Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. <b><i>Results:</i></b> Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. <b><i>Conclusions:</i></b> We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss.

scholarly journals Endogenously produced adiponectin protects cardiomyocytes from hypertrophy by a PPARγ-dependent autocrine mechanism

2010 ◽  
Vol 299 (3) ◽  
pp. H690-H698 ◽  
Author(s):  
Rajesh H. Amin ◽  
Suresh T. Mathews ◽  
Adebisi Alli ◽  
Todd Leff
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Receptor Gene ◽  
Peroxisome Proliferator ◽  
Adrenergic Stimulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Culture Models

In experimental animal and cell culture models, activation of peroxisome proliferator-activated receptor (PPAR) γ in heart has been shown to have beneficial effects on cardiac function and cardiomyocyte physiology. The goal of this study was to identify the signaling pathway by which PPARγ activation protects cardiomyocytes from the deleterious effects of hypertrophic stimuli. In primary cardiomyocyte cultures, we found that genetic or pharmacological activation of PPARγ protected cells from cardiac hypertrophy induced by α-adrenergic stimulation. Examination of gene expression in these cells revealed a surprising increase in the expression of adiponectin in cardiomyocytes and secretion of the high-molecular-weight form of the hormone into media. Using RNAi to block PPARγ-induced adiponectin production or adiponectin receptor gene expression, we found that the PPARγ-mediated anti-hypertrophic effect required cardiomyocyte-produced adiponectin, as well as an intact adiponectin signaling pathway. Furthermore, mice expressing constitutive-active PPARγ and cardiomyocyte specific adiponectin expression were protected from high-fat diet-induced cardiac hypertrophy and remodeling. These findings demonstrate that functional adiponectin hormone can be produced from the heart and raise the possibility that beneficial effects of PPARγ activation in heart could be due in part to local production of adiponectin that acts on cardiomyocytes in an autocrine manner.

scholarly journals Beta-sitosterol upregulated paraoxonase-1 via peroxisome proliferator-activated receptor-γ in irradiated rats

2017 ◽  
Vol 95 (6) ◽  
pp. 661-666 ◽  
Author(s):  
Enas Mahmoud Moustafa ◽  
Noura Magdy Thabet
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Enzyme Activities ◽  
Liver Tissue ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Oxidative Stress Marker ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

This study was designed to evaluate the effect of beta-sitosterol (BS) on the peroxisome proliferator-activated receptor gamma (PPAR-γ) gene expression role in the activity of paraoxonase (PON-1) enzyme in oxidative stress status of irradiated rats. Animals were exposed to whole body γ-radiation single dose 6 Gy and received BS dose (40 mg·(kg body mass)−1·day−1, orally). In liver tissue, gene expression of PPAR-γ ligand was determined. Oxidative stress marker (malondialdehyde, MDA) and antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT), PON-1, and arylesterase (ARE)) were assayed in serum and liver tissue. Also, serum lipid profile (cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c)) was measured. In irradiated animals that received BS, expression of PPAR-γ ligand increase significantly associated with increase in PON-1 and ARE enzyme activities. Also, the activities of SOD, CAT enzymes, and HDL-c levels display elevation. By contrast, significant decrease in MDA content, cholesterol, TG, and LDL-c levels were revealed after BS administration. Our findings in this study provide the evidence that BS has radio-protective effect via regulating the gene expression of PPAR-γ, causing an increase in PON-1 and ARE enzyme activities. This action of BS is due to its free radical scavenging properties, antioxidant effect, lowering of cholesterol, and PPAR-γ agonist properties.

Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells

2007 ◽  
Vol 292 (1) ◽  
pp. G113-G123 ◽  
Author(s):  
Shizhong Zheng ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

scholarly journals Gene expressions of de novo hepatic lipogenesis in feline hepatic lipidosis

2019 ◽  
Vol 22 (6) ◽  
pp. 500-505
Author(s):  
Chiara Valtolina ◽  
Joris H Robben ◽  
Monique E van Wolferen ◽  
Hedwig S Kruitwagen ◽  
Ronald J Corbee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Liver Tissue ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Hepatic Lipidosis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Objectives The aim of this study was to evaluate if de novo hepatic lipid synthesis contributes to fatty acid overload in the liver of cats with feline hepatic lipidosis (FHL). Methods Lipogenic gene expression of peroxisome proliferator-activated receptor-alpha ( PPAR-α), peroxisome proliferator-activated receptor-gamma ( PPAR-γ), fatty acid synthase ( FASN) and sterol regulatory element-binding factor ( SREBF1) were evaluated using quantitative RT-PCR in liver tissue of six cats with FHL and compared with the liver tissue of eight healthy cats. Results In liver tissue, PPAR-α, PPAR-γ and FASN mRNA expression levels were not significantly different ( P >0.12, P >0.89 and P >0.5, respectively) in the FHL group compared with the control group. SREBF1 gene expression was downregulated around 10-fold in the FHL group vs the control group ( P = 0.039). Conclusions and relevance The downregulation of SREBF1 in the liver tissue of cats with FHL does not support the hypothesis that de novo lipogenesis in the liver is an important pathway of fatty acid accumulation in FHL.

Abstract 409: Effects of Angiotensin II Receptor Blocker (ARB) and PPAR-gamma Agonist on Vascular Failure in Patients with Hypertension, Diabetic Mellitus and Chronic Kidney Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hideki Watanabe ◽  
Kunio Nakagawa ◽  
Masaaki Kakihana
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
High Sensitivity ◽  
Ppar Gamma ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Ppar Γ ◽  
Ckd Stage ◽  
Measured Flow

Background: Hypertension (HT), diabetes mellitus (DM), and chronic kidney disease (CKD) are known to be associated with “vascular failure”, which is defined as the integration of endothelial dysfunction and metabolic abnormalities of the vessel wall including inflammation, oxidative stress. We evaluated effects of ARB, calcium channel blocker (CCB), and PPAR-γ agonist on vascular failure in patients with HT, DM and CKD. Methods: Forty eight patients with untreated HT, type 2 DM (HbA1c 6.0 – 6.5%), and CKD (stage 3 or 4) were randomized to receive telmisartan ( Tel. group , n=12), telmisartan and pioglitazone ( Tel. and Pio. group , n=12), amlodipine ( Aml. group , n=12), or amlodipine and pioglitazone ( Aml. and Pio. group , n=12). We measured flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID) of brachial artery, and pulse wave velocity (PWV). We also measured high sensitivity C-reactive peptide (hsCRP) and TBARS levels as indexes of inflammation and oxidative stress. Measurements were performed at baseline, and then at every 6 months after the treatments. Results: Blood pressure was significantly decreased in these groups, and there was no difference among four groups at baseline and during the study. FMD was significantly increased, and PWV, hsCRP, and TBARS were significantly decreased in four groups. However, these improvements were much better in the Tel. and Pio. group than the other groups. NID did not change during the study. Conclusion: Combination therapy with ARB and PPAR-γ agonist was much better in the improvement of vascular failure in patients with HT, DM and CKD as compared with the therapy with ARB alone, CCB alone, or CCB and PPAR-γ agonist.

Activation of peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth

2003 ◽  
Vol 285 (1) ◽  
pp. G20-G30 ◽  
Author(s):  
Jianye Xu ◽  
Yumei Fu ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Liver Injury ◽  
Hepatic Fibrosis ◽  
Stellate Cell ◽  
Healing Process ◽  
Wound Healing Process ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Hepatic fibrogenesis occurs as a wound-healing process after many forms of chronic liver injury. Hepatic fibrosis ultimately leads to cirrhosis if not treated effectively. During liver injury, quiescent hepatic stellate cells (HSC), the most relevant cell type, become active and proliferative. Oxidative stress is a major and critical factor for HSC activation. Activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) inhibits the proliferation of nonadipocytes. The level of PPAR-γ is dramatically diminished along with activation of HSC. Curcumin, the yellow pigment in curry, is a potent antioxidant. The aims of this study were to evaluate the effect of curcumin on HSC proliferation and to begin elucidating underlying mechanisms. It was hypothesized that curcumin might inhibit the proliferation of activated HSC by inducing PPAR-γ gene expression and reviving PPAR-γ activation. Our results indicated that curcumin significantly inhibited the proliferation of activated HSC and induced apoptosis in vitro. We demonstrated, for the first time, that curcumin dramatically induced the gene expression of PPAR-γ and activated PPAR-γ in activated HSC. Blocking its trans-activating activity by a PPAR-γ antagonist markedly abrogated the effects of curcumin on inhibition of cell proliferation. Our results provide a novel insight into mechanisms underlying the inhibition of activated HSC growth by curcumin. The characteristics of curcumin, including antioxidant potential, reduction of activated HSC growth, and no adverse health effects, make it a potential antifibrotic candidate for prevention and treatment of hepatic fibrosis.

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.

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