Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease

Gilde, Andries J.; Fruchart, Jean‐Charles; Staels, Bart

doi:10.1016/j.jacc.2006.04.097

Cited by 34 publications

(27 citation statements)

References 126 publications

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“…PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. Upon ligand activation, PPARs heterodimerize with the retinoid X receptor (RXR) and bind to PPAR response elements (PPREs) in regulatory promoter regions of their target genes (12,13). PPARs can also interact with signaling molecules to regulate gene expression independent of DNA binding (13).…”

Section: Introductionmentioning

confidence: 99%

“…Upon ligand activation, PPARs heterodimerize with the retinoid X receptor (RXR) and bind to PPAR response elements (PPREs) in regulatory promoter regions of their target genes (12,13). PPARs can also interact with signaling molecules to regulate gene expression independent of DNA binding (13). For example, PPARγ impairs phosphorylation (i.e., activation) of ERK (14,15), a MAPK downstream of PDGF-BB/PDGFR-β signaling implicated in SMC proliferation and migration (12).…”

Section: Introductionmentioning

confidence: 99%

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An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

Hansmann¹,

Perez²,

Alastalo³

et al. 2008

J. Clin. Invest.

338

362

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Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARγ and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARγ that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARγ agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPARγ antagonist, and PASMCs isolated from PPARγ-and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARγ, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARγ in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARγ-mediated events could protect against PAH, and PPARγ agonists may reverse PAH in patients with or without BMP-RII dysfunction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

Hansmann¹,

Perez²,

Alastalo³

et al. 2008

J. Clin. Invest.

338

362

View full text Add to dashboard Cite

show abstract

“…For a long time, the PPARα-activating fibrates, a class of amphipathic carboxylic acids, have been used in the treatment of dyslipidemia. In dyslipidemic patients, these drugs improve the plasma lipid profile by lowering triglyceride, and to a lesser extent, low-density lipoprotein (LDL) cholesterol levels and by increasing high-density-lipoprotein (HDL) cholesterol levels [19]. These effects are achieved by a variety of mechanisms, such as an increase in lipoprotein lipase expression, reduction of apolipoprotein CIII expression, inhibition of triglyceride synthesis and very-low-density lipoprotein production.…”

Section: Ppars Drug Targets For Diabetes and Obesitymentioning

confidence: 99%

“…Recently, the concept of the selective peroxisome proliferator-activated receptor modulators (SPPARM) was introduced [19]. SPPARM is a new pharmacological approach that is based on selective receptor-cofactor interactions and differential target gene regulation.…”

Section: Ppars Drug Targets For Diabetes and Obesitymentioning

confidence: 99%

Orphan nuclear receptors in drug discovery

Shi

2007

Drug Discovery Today

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SummaryOrphan nuclear receptors provide a unique resource for uncovering novel regulatory systems that impact human health and provide excellent drug targets for a variety of human diseases. Ligands of nuclear receptors have been used in a number of important therapeutic areas, such as breast cancers, skin disorders, and diabetes. Orphan nuclear receptors, therefore, represent a tremendous opportunity in understanding and treating human diseases. This review highlights advances and potentials of using orphan nuclear receptors, in particular PPARs, Nurr1, RORs, and TLX as targets for drug discovery in diabetes and obesity, neurodegenerative diseases, and other related disorders.

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“…PPAR-α has multiple actions at the level of the liver, which can improve atherogenic dyslipidemia as well as directly modifying the inflammation response at the level of the arterial wall, both resulting in a reduction in atherogenesis [66, 67]. …”

Section: Prevention Of the Metabolic Syndromementioning

confidence: 99%

The Metabolic Syndrome and Cerebrovascular Disease: Suspicion and Evidence

Gil‐Núñez

2007

Cerebrovasc Dis

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The metabolic syndrome (MS) is the combination of factors which, when occurring in an individual, can result in an increased risk of diabetes mellitus (DM) and of episodes of vascular disease. We present a systematic review of the diagnostic criteria, pathology, prevalence and risk of vascular disease (including stroke) associated with the MS and, if the patients have already suffered cerebral ischemia and have the MS and/or DM, the appropriate therapies from which they could benefit.

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Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease

Cited by 34 publications

References 126 publications

An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

Orphan nuclear receptors in drug discovery

The Metabolic Syndrome and Cerebrovascular Disease: Suspicion and Evidence

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