The PPAR-RXR Transcriptional Complex in the Vasculature

Plutzky, Jorge

doi:10.1161/circresaha.110.226860

Cited by 137 publications

(102 citation statements)

References 178 publications

(177 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…RXRs are common heterodimerization partners of other nuclear receptors, and it is known that PPARs form permisive RXR heterodimers, which in some cases synergistically respond to both agonists, RXR and the partner receptor (53). PPARa, PPARb, or PPARg activation can downregulate the expression of CAMs, proinflammatory genes, and reduce leukocyte/endothelial cell interactions (24,29).…”

Section: Discussionmentioning

confidence: 99%

Retinoid X Receptor Agonists Impair Arterial Mononuclear Cell Recruitment through Peroxisome Proliferator-Activated Receptor-γ Activation

Sanz

Albertos

Otero

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)α on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXRα expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-α. Interestingly, under physiological flow conditions, TNF-α–induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-α–induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-α and MCP-1 release. Suppression of RXRα expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-κB pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXRα/peroxisome proliferator-activated receptor (PPAR)γ interaction, since endothelial PPARγ silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPARγ interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-α–induced mononuclear leukocyte arrest by 60–65%. In vivo, bexarotene dose-dependently inhibited TNF-α–induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Retinoid X Receptor Agonists Impair Arterial Mononuclear Cell Recruitment through Peroxisome Proliferator-Activated Receptor-γ Activation

Sanz

Albertos

Otero

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The inflammatory processes characterized by the adhesion of monocytes and the secretion of inflammatory cytokines alter vascular function [61]. PPARα activation limits the inflammatory response of endothelial cells and VSMCs by inhibiting pro-inflammatory signaling pathways and improving the lipid profile, thus contributing to the anti-atherogenic action of PPARα agonists [62]. The absence of PPARα in mice causes a prolonged response to inflammatory stimuli [63].…”

Section: Pparα In Vascular Injurymentioning

confidence: 99%

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

Yang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Three members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα, PPARγ, and PPARβ/δ, have been investigated widely over the past few decades. Although the roles of these PPARs and their agonists/antagonists were defined in clinical and basic studies, the conflicting results from these studies indicate that more analysis is needed to understand the roles of PPARs. PPARα is a ligand-activated transcription factor that contributes to the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. In this review, we focus on the function and mechanisms of PPARα in the cardiovascular system under various pathological conditions, including vascular and heart injury, blood pressure regulation, and lipid disorder-related cardiovascular injury, as well as its polymorphisms and pharmacogenetic associations with cardiovascular diseases. The anti-inflammatory effect of PPARα in cardiovascular injury is mainly through inhibition of pro-inflammatory signaling pathways and improvement of the lipid profile. Moreover, PPARα also modulates the activity of endothelial nitric oxide synthase and resets the renin-angiotensin system to regulate vascular tone. PPARα gene variants appear to be associated with some cardiovascular risk factors, such as higher plasma lipid levels, cardiac growth, and increased risk of coronary artery disease. Nowadays, novel PPARα drugs with broad safety margins and therapeutic potential for metabolic syndrome and cardiovascular diseases are being developed and applied in the clinical setting. The insights from the current review shed new light on areas of further study and provide a better understanding of the role of PPARα in cardiovascular diseases.

show abstract

“…PPARs comprise a family of ligand-activated transcription factors that belong to the nuclear receptor superfamily (44). Following engagement by endogenous or synthetic ligands, PPARs translocate to the nucleus where they undergo heterodimerization with retinoid X receptors by binding to peroxisome proliferator response elements in the promoter region of target genes.…”

Section: ϫ/ϫ (Iii Iv) Mice Following Inoculation With Pbs Vehicle Comentioning

confidence: 99%

Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-γ

Park

Guang

Blanchard

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

MUC1 is a membrane-tethered mucin expressed on the apical surface of epithelial cells. Our previous report (Guang W, Ding H, Czinn SJ, Kim KC, Blanchard TG, Lillehoj EP. J Biol Chem 285: 20547–20557, 2010) demonstrated that expression of MUC1 in AGS gastric epithelial cells limits Helicobacter pylori infection and reduces bacterial-driven IL-8 production. In this study, we identified the peroxisome proliferator-associated receptor-γ (PPARγ) upstream of MUC1 in the anti-inflammatory pathway suppressing H. pylori- and phorbol 12-myristate 13-acetate (PMA)-stimulated IL-8 production. Treatment of AGS cells with H. pylori or PMA increased IL-8 levels in cell culture supernatants compared with cells treated with the respective vehicle controls. Prior small interfering (si)RNA-induced MUC1 silencing further increased H. pylori - and PMA-stimulated IL-8 levels compared with a negative control siRNA. MUC1-expressing AGS cells pretreated with the PPARγ agonist troglitazone (TGN) had reduced H. pylori - and PMA-stimulated IL-8 levels compared with cells treated with H. pylori or PMA alone. However, following MUC1 siRNA knockdown, no differences in IL-8 levels were seen between TGN/ H. pylori and H. pylori -only cells or between TGN/PMA and PMA-only cells. Finally, TGN-treated AGS cells had increased Muc1 promoter activity, as measured using a Muc1-luciferase reporter gene, and greater MUC1 protein levels by Western blot analysis, compared with vehicle controls. These results support the hypothesis that PPARγ stimulates MUC1 expression by AGS cells, thereby attenuating H. pylori - and PMA-induced IL-8 production.

show abstract

The PPAR-RXR Transcriptional Complex in the Vasculature

Cited by 137 publications

References 178 publications

Retinoid X Receptor Agonists Impair Arterial Mononuclear Cell Recruitment through Peroxisome Proliferator-Activated Receptor-γ Activation

Retinoid X Receptor Agonists Impair Arterial Mononuclear Cell Recruitment through Peroxisome Proliferator-Activated Receptor-γ Activation

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-γ

Contact Info

Product

Resources

About