PPARα Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells

Marx, Nikolaus; Sukhova, Galina K.; Collins, Tucker; Libby, Peter; Plutzky, Jorge

doi:10.1161/01.cir.99.24.3125

Cited by 572 publications

(407 citation statements)

References 38 publications

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“…In vascular smooth muscle cells and endothelial cells, previous reports showed that, in contrast to PPARa agonists, PPARg agonists did not influence cytokine-induced activation of NF-kB. 35,36 In contrast, our present report showed the potential of PPARg to suppress NFkB in adipocytes. The reason for the lack of NF-kB suppression by PPARg agonists in vascular cells is currently unclear, but may simply be due to the fact that the expression level of PPARg is low in these cell types.…”

Section: Selective Loss Of Adipocytes By Tnf-a M Tamai Et Alcontrasting

confidence: 90%

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Tamai

Shimada

Hiramatsu

et al. 2010

Laboratory Investigation

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Tumor necrosis factor-a (TNF-a) is a key regulator of adipose tissue mass, but mechanisms underlying this effect have not been fully elucidated. We found that exposure to TNF-a caused a significant decrease in the number of adipocytes, but not preadipocytes. Subsequent experiments revealed that TNF-a selectively deleted adipocytes through induction of apoptosis. Following exposure to TNF-a, rapid activation of nuclear factor-kB (NF-kB) was observed only in preadipocytes, but not in adipocytes. Inhibition of NF-kB rendered preadipocytes susceptible to TNF-a-induced apoptosis, suggesting that different activity of NF-kB is the determinant for the distinct apoptotic responses. During adipocyte differentiation, expression and activity of peroxisome proliferator-activated receptor-g (PPARg) were upregulated. Treatment of preadipocytes with a PPARg agonist attenuated NF-kB activation and rendered the cells vulnerable to TNF-a-induced apoptosis. Conversely, treatment of adipocytes with a PPARg antagonist enhanced NF-kB activation and conferred resistance to TNF-a-induced apoptosis, suggesting involvement of PPARg in the suppression of NF-kB in adipocytes. We also found that, following differentiation, expression and activity of CCAAT/ enhancer binding protein (C/EBP), especially C/EBPa and C/EBPb, were upregulated in adipocytes. Overexpression of individual C/EBPs significantly inhibited activation of NF-kB in preadipocytes. Furthermore, transfection with siRNA for C/EBPa or C/EBPb enhanced activity of NF-kB in adipocytes, suggesting that C/EBP is also involved in the repression of NF-kB in adipocytes. These results suggested novel mechanisms by which TNF-a selectively deletes adipocytes in the adipose tissue. The C/EBP-and PPARg-mediated suppression of NF-kB may contribute to TNF-a-related loss of adipose tissue mass under certain pathological situations, such as cachexia.

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Section: Selective Loss Of Adipocytes By Tnf-a M Tamai Et Alcontrasting

confidence: 90%

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Tamai

Shimada

Hiramatsu

et al. 2010

Laboratory Investigation

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“…Vascular endothelial cells, vascular smooth muscle cells and monocyte/macrophages express PPARα. It has been shown both in vitro [46] and in vivo [47] that fibrates modulate monocyte recruitment by limiting the expression of leucocyte adhesion molecules on the surface of both endothelial cells and infiltrating mononuclear cells. Moreover, PPARα agonists reduce the release of matrix metalloproteinases by monocyte/macrophages [48].…”

Section: Discussionmentioning

confidence: 99%

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

Sahebkar

Giua

Pedone

et al. 2016

Pharmacological Research

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Flow-mediated dilation (FMD) of the brachial artery reflects endothelium-dependent vasodilator function; since it correlates with coronary endothelial function, its reduction could predict cardiovascular events. Several studies have investigated the potential impact of fibrates therapy on endothelial function, but clinical findings have not been fully consistent. We aimed to conduct a meta-analysis of randomized placebo-controlled trials in order to clarify whether fibrate therapy could improve endothelial function. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of fibrates on endothelial function as estimated by FMD. A randomeffects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk of bias evaluation, and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. Fifteen trials with a total of 556 subjects met the eligibility criteria. Fibrate 3 therapy significantly improves FMD (weighted mean difference [WMD]: 1.64%, 95% CI: 1.15, 2.13, p < 0.001) and the result was confirmed in both subgroups with treatment durations ≤8 weeks (WMD: 1.35%, 95% CI: 0.85, 1.86, p < 0.001) and >8 weeks (WMD: 2.55%, 95% CI: 1.21, 3.89, p < 0.001). When the analysis was stratified according to the fibrate type, a significant effect was observed with fenofibrate but not with gemfibrozil, though difference between the two subgroups was not significant. Meta-analysis of data from trials where nitrate mediated dilation (NMD) was available did not suggest a significant change in NMD following treatment with fibrates. The results of this meta-analysis suggest that fibrates may exert beneficial effects on endothelial function, even over a short-term treatment course.

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“…However, PPAR␣ activation has been shown to inhibit IL-6 and 6-keto-PGF 1␣ secretion from primary aortic smooth muscle cells. In addition, PPAR␣ ligands have been reported to inhibit cytokine-induced genes such as vascular cell adhesion molecule-1 and tissue factor in human endothelial cells and monocytes, respectively (48,49). It has been suggested that PPAR␣ may have an important immunomodulatory role because PPAR␣ knockout mice exhibit an exacerbated inflammatory response (18).…”

Section: Discussionmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptors in Human Airway Smooth Muscle Cells Has a Superior Anti-inflammatory Profile to Corticosteroids: Relevance for Chronic Obstructive Pulmonary Disease Therapy

Patel¹,

Belvisi²,

Bishop‐Bailey

et al. 2003

The Journal of Immunology

119

120

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Airway smooth muscle is actively involved in the inflammatory process in diseases such as chronic obstructive pulmonary disease and asthma by 1) contributing to airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF and G-CSF, which promotes the survival and activation of infiltrating leukocytes. Thus, the identification of novel anti-inflammatory pathways in airway smooth muscle will have important implications for the treatment of inflammatory airway disease. This study identifies such a pathway in the activation of peroxisome proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic agents in the treatment of diabetes; however, their role in human airway disease is unknown. We demonstrate, for the first time, that human airway smooth muscle cells express PPARα and -γ subtypes. Activation of PPARγ by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPARγ activation, like dexamethasone, inhibits the release of GM-CSF. However, PPARγ ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPARγ activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases.

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PPARα Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells

Abstract: Human ECs express PPARalpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARalpha.

Cited by 572 publications

References 38 publications

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

Activation of Peroxisome Proliferator-Activated Receptors in Human Airway Smooth Muscle Cells Has a Superior Anti-inflammatory Profile to Corticosteroids: Relevance for Chronic Obstructive Pulmonary Disease Therapy

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