PPARδ regulates multiple proinflammatory pathways to suppress atherosclerosis

Barish, Grant D.; Atkins, Annette R.; Downes, Michael; Olson, Peter; Chong, Ling Wa; Nelson, Mike; Zou, Yuhua; Hwang, Hoosang; Kang, Heonjoong; Curtiss, Linda K.; Evans, Ronald M.; Lee, Chih‐Hao

doi:10.1073/pnas.0711875105

Cited by 182 publications

(164 citation statements)

References 54 publications

(63 reference statements)

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“…S3). Indeed, nuclear receptors belonging to the PPAR family have emerged as relevant in anti-inflammatory signaling mechanisms and may bind lipids (16). For example, oxidized fatty acids at concentrations in the micromolar range can activate PPARγ, which possesses an unusually large ligand-binding cavity that accommodates a wide range of molecules rather than a single ligand (21).…”

Section: Discussionmentioning

confidence: 99%

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Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Krishnamoorthy

Recchiuti

Chiang

et al. 2010

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

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631

710

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Endogenous mechanisms that act in the resolution of acute inflammation are essential for host defense and the return to homeostasis. Resolvin D1 (RvD1), biosynthesized during resolution, displays potent and stereoselective anti-inflammatory actions, such as limiting neutrophil infiltration and proresolving actions. Here, we demonstrate that RvD1 actions on human polymorphonuclear leukocytes (PMNs) are pertussis toxin sensitive, decrease actin polymerization, and block LTB 4 -regulated adhesion molecules (β2 integrins). Synthetic [ 3 H]-RvD1 was prepared, which revealed specific RvD1 recognition sites on human leukocytes. Screening systems to identify receptors for RvD1 gave two candidates-ALX, a lipoxin A 4 receptor, and GPR32, an orphan -that were confirmed using a β-arrestin-based ligand receptor system. Nuclear receptors including retinoid X receptor-α and peroxisome proliferator-activated receptor-α, -δ, -γ were not activated by either resolvin E1 or RvD1 at bioactive nanomolar concentrations. RvD1 enhanced macrophage phagocytosis of zymosan and apoptotic PMNs, which increased with overexpression of human ALX and GPR32 and decreased with selective knockdown of these G-protein-coupled receptors. Also, ALX and GPR32 surface expression in human monocytes was up-regulated by zymosan and granulocyte-monocyte-colony-stimulating factor. These results indicate that RvD1 specifically interacts with both ALX and GPR32 on phagocytes and suggest that each plays a role in resolving acute inflammation.inflammation | leukocytes | lipid mediators | resolution | polyunsaturated fatty acids

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Section: Discussionmentioning

confidence: 99%

“…Nuclear receptors may evoke anti-inflammatory responses (16). Therefore, we sought to determine whether RvD1 interacts with specific nuclear receptors.…”

Section: Rvd1mentioning

confidence: 99%

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Krishnamoorthy

Recchiuti

Chiang

et al. 2010

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

Self Cite

631

710

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“…This dose was chosen based on the results of the previous in vivo studies demonstrating selectivity of GW501516 as a PPARd agonist. 33,35 Investigator was not blinded as to which mouse belonged to control group and which belonged to treated group. Brain tissues were collected after mice were killed by injection of an overdose of pentobarbital (250 mg/kg body weight, i.p.).…”

Section: Materials and Methods Micementioning

confidence: 99%

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

Santhanam

Lü

et al. 2016

J Cereb Blood Flow Metab

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We tested hypothesis that activation of the prostacyclin (PGI 2 ) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI 2 , iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPa (sAPPa). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor d (PPARd) in human brain microvascular endothelial cells. PPARd-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARd) upregulated ADAM10 and increased production of sAPPa. Genetic deletion of endothelial PPARd (ePPARd À/À ) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPa. In vivo treatment with GW501516 increased sAPPa content in hippocampus of wild type mice but not in hippocampus of ePPARd À/À mice. Our findings identified previously unrecognized role of IP-PPARd signal transduction pathway in the production of sAPPa in cerebral microvasculature.

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“…Recently, PPAR agonists have been reported to be "exercise mimetics" and increase exercise endurance without exercise in mice, suggesting a unique therapeutic approach for life-style-related disease 113) . PPAR also regulates multiple pro-inflammatory pathways to suppress atherosclerosis 114) , and plays some roles in angiogenesis with endothelial progenitor cells 115) . Recent investigations have revealed that PPAR is intimately involved in metabolic regulation and atherosclerosis.…”

Section: Pparmentioning

confidence: 99%

Retinoid X Receptor Heterodimer Variants and Cardiovascular Risk Factors

Nohara

Kobayashi

Mabuchi

2009

JAT

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Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis. This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia.

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PPARδ regulates multiple proinflammatory pathways to suppress atherosclerosis

Cited by 182 publications

References 54 publications

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

Retinoid X Receptor Heterodimer Variants and Cardiovascular Risk Factors

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