Macrophages in Human Atheroma Contain PPARγ

Marx, Nikolaus; Sukhova, Galina K.; Murphy, Christian; Libby, Peter; Plutzky, Jorge

doi:10.1016/s0002-9440(10)65540-x

Cited by 496 publications

(95 citation statements)

References 35 publications

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“…Rexinoids activate RXR in PPAR heterodimers, thereby mimicking some effects of PPAR activation. PPAR␥, which is almost absent in normal arteries, has been shown to be expressed in atherosclerotic lesions in human and mouse (12)(13)(14). Previous in vitro studies suggested a key role of PPAR␥ in inducing macrophage differentiation and foam cell formation (13,15).…”

Section: Resultsmentioning

confidence: 98%

“…(C) Representative photographs of atherosclerosis in the aorta of apoE Ϫ͞Ϫ mice, a relevant section from an untreated apoE Ϫ͞Ϫ mouse (control), and an equivalent section of an apoE-deficient mouse after receiving GW2331 (PPAR␣͞␥ coagonist) or LG100364 (RXR agonist). production of matrix metalloproteinases (14), vascular cell adhesion molecule, and intercellular adhesion molecule (19). Furthermore, PPAR␥ agonists are reported to inhibit migration of vascular smooth muscle cells (20) as well as monocyte͞ macrophage homing (19) to atherosclerotic plaques.…”

Section: Resultsmentioning

confidence: 99%

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Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Claudel

Leibowitz

Fiévet

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

272

175

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A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E ؊͞؊ mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)␥ and a dual agonist of both PPAR␣ and PPAR␥ had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXR␣ and ␤ double ؊͞؊, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR͞LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR͞LXR agonists in prevention and treatment of atherosclerosis. R etinoid X receptors (RXRs) are ubiquitously expressed nuclear receptors that heterodimerize with a number of other receptors (e.g., thyroid hormone receptor, vitamin D receptor, retinoic acid receptors, etc.; refs. 1 and 2). The elucidation of RXRs biological activity has advanced significantly through the characterization of rexinoids, high-affinity selective synthetic ligands for RXRs (1, 2). The use of rexinoids led to the demonstration that RXRs are active and permissive signaling molecules in heterodimers with the farnesol X receptor (FXR) [or bile acid receptor (BAR)], the liver X receptors (LXRs), and the peroxisome proliferatoractivated receptors (PPARs). The simultaneous activation of several permissive heterodimers underlies in part RXRs pleiotropic functions, affecting numerous receptor signaling pathways, and ranges from the control of cell proliferation, differentiation, and apoptosis (3) to the regulation of glucose and lipid metabolism (4). This pivotal role of the various permissive RXR heterodimers is in fact an emerging theme in multiple metabolic pathways. Heterodimers between RXR and PPAR␥, PPAR␣, LXR␣, and FXR͞BAR respectively inf luence glucose, triglyceride, cholesterol, and bile acid homeostasis. Dysregulation of these homeostatic control pathways can result in common metabolic disorders such as obesity, type 2 diabetes, and hyperlipidemia, which are often complicated by the development of atherosclerosis.In view of the potential implication of RXRs in various metabolic pathways implicated in atherosclerosis, we studied whether modulating the activity of these receptors or of some of their heterodimers affects the development of atherosclerosis in apolipoprotein (apo)E-deficient mice. We demonstrate here that the administration of rexinoids significantly attenuates atherosclerosis development, and we show that this effect might be linked to the activation of reverse cholesterol transpor...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Claudel

Leibowitz

Fiévet

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

272

175

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“…PPARγ has had inhibitory effects on VSMC proliferation and migration133, 134 as well as EC growth and migration 135. PPARγ activation reduces monocyte recruitment to atherosclerotic plaques 136. PPARγ also has a modulatory effect on inflammation and is known to decrease monocyte/macrophage production of several inflammatory cytokines 137.…”

Section: Implication Of Noncanonical Wnt Signaling In Vcmentioning

confidence: 99%

Atherosclerotic Calcification: Wnt Is the Hint

Albanese

Khan

Barratt

et al. 2018

JAHA

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“…scavenger receptor expression such as CD36 (4, 6, 7), and this led to the supposition that PPAR␥ activation may promote foam cell formation, a known atherogenic process characterized by cholesterol ester droplet accumulation in macrophages (27). In this experiment, we further investigated the influence of both Cy-3-g and Pn-3-g on AcLDL-induced transformation of mouse peritoneal macrophages into foam cells.…”

Section: Treatment Of Anthocyanin Alone Does Not Influence Foam Cell mentioning

confidence: 99%

Anthocyanins Induce Cholesterol Efflux from Mouse Peritoneal Macrophages

Xia

Hou

Zhu

et al. 2005

Journal of Biological Chemistry

132

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It is widely accepted that stimulation of reverse cholesterol transport, the efflux of excess cholesterol from peripheral tissues and transferring it to the liver for biliary excretion, is becoming an important component in reducing excess cholesterol deposition in atherosclerotic plaques. The ATP-binding cassette transporter has been identified as a key regulator of macrophage cholesterol efflux and apoAI-mediated reverse cholesterol transport. In vivo studies have documented anthocyanins, a large group of naturally phenolic compounds rich in plants, possess substantial capacities in improving plasma cholesterol levels. In this study, we investigated the potential role of anthocyanins in modulating cholesterol efflux from mouse peritoneal macrophages and macrophage-derived foam cells and the possible molecular mechanism linking ABCA1 to cholesterol efflux. Incubation of the mouse peritoneal macrophages and macrophage-derived foam cells with cyanidin-3-O-␤-glucoside and peonidin-3-O-␤-glucoside led to dose-dependent (1-100 M) induction in cholesterol efflux and ABCA1 mRNA expression, and this effect could be blocked by the ABCA1 inhibitor 4,4-diisothiocyanatostilbene-2,2-disulfonic acid, disodium salt, and a general inhibitor of gene transcription actinomycin D. Treatment of the macrophages with anthocyanins also activated peroxisome proliferator-activated receptor ␥, liver X receptor ␣ mRNA expression, and their mediated gene expression. Addition of geranylgeranyl pyrophosphate ammonium salt or GW9662 markedly inhibited the anthocyanin-induced increase of ABCA1 gene expression and apoAI-mediated cholesterol efflux. These data demonstrated that anthocyanin induces cholesterol efflux from mouse peritoneal macrophages and macrophage-derived foam cells and that stimulation of cholesterol efflux by anthocyanin is mediated, at least in part, by peroxisome proliferator-activated receptor ␥-liver X receptor ␣-ABCA1 signaling pathway activation. Atherosclerosis (AS)2 is a multifactorial cardiovascular disease, and its pathogenesis is not fully demonstrated (1, 2). Many studies (3,4) suggested that macrophages played critical pathogenic roles in the formation of atherosclerotic lesions. Fatty streaks of atherosclerosis contain large numbers of macrophage foam cells derived from circulating monocytes that adhere to activated endothelium and migrate into the artery wall (5). These cells subsequently differentiate into macrophages that express the scavenger receptor A gene, as well as other scavenger receptors that mediate the uptake of large amounts of cholesterol (6). As these receptors are not subject to negative regulation by high levels of intracellular cholesterol, massive accumulation of cholesterol esters can occur in macrophages, resulting in foam cell formation. This pathophysiological phenomenon is the typical character of the early stage in the development of AS. Now, it is widely accepted that the removal of excess free cholesterol from arterial cells is very important for maintaining cellular cholesterol homeo...

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Macrophages in Human Atheroma Contain PPARγ

Cited by 496 publications

References 35 publications

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Atherosclerotic Calcification: Wnt Is the Hint

Anthocyanins Induce Cholesterol Efflux from Mouse Peritoneal Macrophages

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