PPARα and PPARδ activators inhibit cytokine-induced nuclear translocation of NF-κB and expression of VCAM-1 in EAhy926 endothelial cells

Rival, Yves; Benéteau, Nathalie; Taillandier, Thierry; Pezet, Mylène; Dupont-Passelaigue, Elisabeth; Patoiseau, Jean François; Junquéro, Didier; Colpaert, Françis C.; Delhon, A.

doi:10.1016/s0014-2999(01)01589-8

Cited by 174 publications

(131 citation statements)

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“…44 Our study further showed that rosiglitazone served its anti-inflammatory actions by interfering with the PKC and NF-kB signalings, which are also firmly supported by the earlier findings. 45,46 In summary, PPARg agonist, rosiglitazone, exerts its antiinflammatory effect by interfering with the TLR4-dependent signaling pathway (ERK1/2/TLR4/IP-10/PKC/NF-kB). These findings provide new mechanisms to beneficial effects of rosiglitazone in the prevention and treatment of cardiovascular disease including atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

Liu

Wang

et al. 2009

Laboratory Investigation

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Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Angiotensin II (Ang II) is a critical factor in inflammatory responses, so as to promote the pathogenesis of atherosclerosis. Toll-like receptor 4 (TLR4) activates signaling pathways leading to the expression of pro-inflammatory cytokines implicated in the etiology of atherosclerosis. Peroxisome proliferator-activated receptor g (PPARg) agonists are considered to be important in modulating vascular inflammation and atherosclerosis. Herein, we investigated the modulatory effects of rosiglitazone on Ang II-mediated inflammatory responses both in vivo and in vitro. We also examined whether TLR4-dependent signaling pathway was involved in the inhibitory effects of rosiglitazone on Ang II-induced pro-inflammatory responses in vascular smooth muscle cells (VSMCs). Male Sprague-Dawley rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Systolic blood pressure rise in Ang II-infused rats was attenuated by rosiglitazone. Rosiglitazone also reduced Ang II-induced generation of pro-inflammatory mediators (TLR4, matrix metalloproteinase-9 and tumor necrosis factor-a), but enhanced production of anti-inflammatory mediators (PPARg and 6-keto-PGF 1a ) both in vivo and in vitro. Furthermore, treatment of VSMCs with both the TLR4 inhibitor and TLR4 small-interfering RNA (siRNA) showed that the modulatory effects of rosiglitazone on Ang II-mediated inflammatory responses in VSMCs were related to TLR4. Treatment of the cells with rosiglitazone had little effect on Ang II receptors expression (AT1 and AT2), but downregulated AT1-dependent ERK1/2 activation. Then, treatment of VSMCs with TLR4 siRNA, interferon-gamma-inducible protein 10 (IP-10) siRNA and with the special protein kinase C (PKC) inhibitor further revealed that the signaling pathway (TLR4/IP-10/PKC/NF-kB) was involved in the inhibitory effects of rosiglitazone on Ang II-induced pro-inflammatory responses in VSMCs. In conclusion, TLR4 may be a drug target involved in the ameliorative effects of PPARg agonist, rosiglitazone, on Ang II-mediated inflammatory responses in VSMCs. Moreover, rosiglitazone exerts its anti-inflammatory effect by interfering with the TLR4-dependent signaling pathway (ERK1/2/TLR4/IP-10/PKC/NF-kB) to prevent and treat atherosclerotic diseases.

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Section: Discussionmentioning

confidence: 99%

PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

Liu

Wang

et al. 2009

Laboratory Investigation

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“…Anti-inflammatory activity of PPARβ/δ and/or PPARβ/δ ligands has been shown in a number of different models including immune cells, colon epithelium, macrophages, cardiomyocytes, keratinocytes, myoblasts, endothelial cells, nerve tissue and hepatocytes Graham et al 2005;Hollingshead et al 2007b;Jakobsen et al 2006;Kim et al 2006;Nagasawa et al 2006;Peters et al 2000;Polak et al 2005;Rival et al 2002;Schmuth et al 2004;Welch et al 2003;Woo et al 2006). There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

et al. 2008

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The development of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands for the treatment of diseases including metabolic syndrome, diabetes and obesity has been hampered due to contradictory findings on their potential safety. For example, while some reports show that ligand activation of PPARβ/δ promotes the induction of terminal differentiation and inhibition of cell growth, other reports suggest that PPARβ/δ ligands potentiate tumorigenesis by increasing cell proliferation. Some of the contradictory findings could be due in part to differences in the ligand examined, the presence or absence of serum in cell cultures, differences in cell lines, or differences in the method used to quantify cell growth. For these reasons, this study examined the effect of ligand activation of PPARβ/δ on cell growth of two human cancer cell lines, MCF7 (breast cancer) and UACC903 (melanoma) in the presence or absence of serum using two highly specific PPARβ/δ ligands, GW0742 or GW501516. Culturing cells in the presence of either GW0742 or GW501516 caused upregulation of the known PPARβ/δ target gene angiopoetin-like protein 4 (ANGPTL4). Inhibition of cell growth was observed in both cell lines cultured in the presence of either GW0742 or GW501516, and the presence or absence of serum had little influence on this inhibition. Results from the present studies demonstrate that ligand activation of PPARβ/δ inhibits the growth of both MCF7 and UACC903 cell lines and provide further evidence that PPARβ/δ ligands are not mitogenic in human cancer cell lines.

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“…To answer the question whether the endogenous PPAR␣ would be also inhibited by the overexpressed Trx, the basal activity of PPAR␣ was determined in HeLa, HepG2, and EA.hy.926 cells transfected with pcDNA-Trx or GAL4-Trx using (PPRE) 3 -TK-Luc as a reporter. It was reported that all of these cell types have endogenous PPAR␣ (Rival et al, 2002). As shown in Figure 5C, the procytoplasmic Trx slightly, whereas the pronuclear Trx significantly inhibited the basal PPAR␣ activity.…”

Section: Down-regulation Of Ppar␣ Transcriptional Activity By Ectopicmentioning

confidence: 62%

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor α Transcriptional Activity

Liu

Shen

2006

MBoC

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PPAR␣, a member of the nuclear receptor superfamily, and thioredoxin, a critical redox-regulator in cells, were found to form a negative feedback loop, which autoregulates transcriptional activity of PPAR␣. Thioredoxin was identified as a target gene of PPAR␣. Activation of PPAR␣ leads to increase of thioredoxin expression as well as its translocation from cytoplasm to nucleus, whereas ectopic overexpression of thioredoxin in the nucleus dramatically inhibited both constitutive and ligand-dependent PPAR␣ activation. As PPAR␣-target genes, the expression of muscle carnitine palmitoyltransferase I, medium chain acyl CoA dehydrogenase, and apolipoprotein A-I were significantly down-regulated by nucleus-targeted thioredoxin at transcriptional or protein level. The suppression of PPAR␣ transcriptional activity by Trx could be enhanced by overexpression of thioredoxin reductase or knockdown of thioredoxin-interacting protein, but abrogated by mutating the redox-active sites of thioredoxin. Mammalian one-hybrid assays showed that thioredoxin inhibited PPAR␣ activity by modulating its AF-1 transactivation domain. It was also demonstrated by electrophoretic mobility-shift assay that thioredoxin inhibited the binding of PPAR␣ to the PPAR-response element. Together, it is speculated that the reported negative-feedback loop may be essential for maintaining the homeostasis of PPAR␣ activity. INTRODUCTIONAs the first identified genetic sensor for fats, PPAR␣ is a ligandactivated transcription factor belonging to the nuclear receptor superfamily. The target genes of PPAR␣ are relatively homogenous group of genes that participate in various aspects of lipid catabolism such as fatty acid uptake through membranes, fatty acid binding in cells, fatty acid oxidation in microsomes, peroxisomes and mitochondria, and lipoprotein assembly and transportation (Lemberger et al., 1996). The significance of PPAR␣ in physiology and disease is evidenced by the fact that it and PPAR␥, another subtype of PPARs, are molecular targets for the lipid-lowering fibrate drugs and insulin-sensitizing thiazolidinedione (TZD), respectively (Evans et al., 2004). Besides activation of PPAR␣ by fatty acid and various exogenous ligands such as fibrates, the regulation of the PPAR␣ transcription activity by coactivators (Dowell et al., 1997), corepressors (Dowell et al., 1999), other transcription factors (TFs; Zhou et al., 1999), and posttranslational modifications including phosphorylation (Juge-Aubry et al., 1999) and ubiquination (Blanquart et al., 2002) have been extensively studied. However, redox regulation of PPAR␣ activity has not been reported so far.Multicellular organisms have evolved complex homeostatic mechanisms to sense and respond to a diverse range of exogenous and endogenous signals. It may be reasonable to expect some mechanisms that rapidly sense and tightly control the activity of PPAR␣ according to metabolic needs under normal physiological condition. Degradation of PPAR␣ by the ubiquitin-proteasome system and decrease of the ubiquitinat...

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PPARα and PPARδ activators inhibit cytokine-induced nuclear translocation of NF-κB and expression of VCAM-1 in EAhy926 endothelial cells

Cited by 174 publications

References 33 publications

PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor α Transcriptional Activity

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