Has Angiogenesis Been Invited to the PPARty?

doi:10.1006/jmcc.2002.2029

Journal of Molecular and Cellular Cardiology

Volume 34, Issue 7, July 2002, Pages 713-716

https://doi.org/10.1006/jmcc.2002.2029 Get rights and content

Abstract

P. M. Barger. Has Angiogenesis Been Invited to the PPARty? Journal of Molecular and Cellular Cardiology (2002) 34, 713–716.

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Cited by (6)

Structural basis for iloprost as a dual peroxisome proliferator-activated receptor α/δ agonist
2011, Journal of Biological Chemistry
Citation Excerpt :
The pharmacologic actions of PPARs are mediated first through their LBDs, which bind ligands, then recruit nuclear receptor coactivators (or corepressors) to regulate expression of the downstream target genes. Interestingly, PPARs have been revealed as important regulators in angiogenesis (12, 13). Indeed, some effects of iloprost in vivo, like angiogenesis and up-regulation of vascular endothelial growth factor, function through PPARα-dependent mechanisms (14, 15).
Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPARα ligand-binding domain and PPARδ ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPARα/δ by this prostacyclin analog. In addition to conserved contacts for all PPARα ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPARα/δ interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.
PPAR gamma: A novel pharmacological target against retinal and choroidal neovascularization
2005, Journal Francais d'Ophtalmologie
Le PPARγ (Peroxisome Proliferator-activated Receptor gamma) est un récepteur nucléaire qui contrôle la transcription de nombreux gènes impliqués dans la différenciation, la prolifération et l’apoptose de divers types cellulaires. D’abord découvert dans les adipocytes dont il stimule la différenciation, il a été ensuite caractérisé dans l’endothélium des vaisseaux, notamment dans les cellules endothéliales choroïdiennes et rétiniennes. Les agonistes qui se lient au PPARγ et stimulent son activité transcriptionnelle sont des lipides endogènes comme l’acide lysophosphatidique et la 15-d-PGJ2, ainsi que des agents pharmacologiques de synthèse, les thiazolidinediones utilisées dans le traitement du diabète de type 2. Ces ligands inhibent la néovascularisation de la choroïde et de la rétine dans différents modèles expérimentaux chez l’animal, en bloquant notamment l’expression des récepteurs du facteur de croissance endothélial (VEGF). La haute affinité de certains agonistes et leur faible masse molaire, favorable à une bonne biodisponibilité, font du PPARγ une nouvelle cible potentielle pour des agents angiostatiques destinés en particulier au traitement de la dégénérescence maculaire liée à l’âge et de la rétinopathie diabétique.
PPARγ (peroxisome proliferator-activated receptor gamma) is a nuclear receptor that regulates the transcription of numerous genes involved in the differentiation, proliferation and apoptosis of various cell types. It was initially discovered in adipocytes as a differentiation agent, then was characterized in vascular endothelium and recently in choroidal and retinal endothelial cells. Agonists that bind to PPARγ and stimulate its transcriptional activity are endogenous lipids such as lysophosphatidic acid and 15-d-PGJ2 as well as the synthetic pharmacological compounds, thiazolidinediones, used for treating type 2 diabetes. These ligands prevent choroidal and retinal neovascularization in several experimental animal models, notably through the inhibition of vascular endothelial growth factor (VEGF) receptor expression. Because of the high affinity and the low molecular weight of agonists, suitable for good bioavailability, PPARγ could potentially be a novel pharmacological target of angiostatic agents, particularly useful to treat age-related macular degeneration and diabetic retinopathy.
Comparative analysis of the in vivo angiogenic properties of stable prostacyclin analogs: A possible role for peroxisome proliferator-activated receptors
2004, Journal of Molecular and Cellular Cardiology
Objective. – Until recently, prostacyclin (PGI₂) biological activities were thought to be exclusively mediated by cell surface receptors named IP. Recent studies have instead identified a novel pathway of PGI₂ signaling, occurring through activation of peroxisome proliferator-activated receptors (PPARs) located in the nucleus. The availability of stable PGI₂ analogs with different affinity for IP receptors and PPARs provides the possibility to test the importance and function of this dual pathway in vitro and in vivo. In this study, the in vivo angiogenic properties of different PGI₂ analogs and the potential relationship between PPAR-mediated pathways, vascular endothelial growth factor (VEGF), and angiogenesis were investigated.
Methods and results. – By using the murine corneal model of angiogenesis, we found that PGI₂ analogs able to act on nuclear PPARs, such as iloprost and carbaprostacyclin (cPGI), induce angiogenesis in vivo. In contrast, cicaprost, a PGI₂ analog that only acts on IP receptors, has no in vivo angiogenic activity. Interestingly, angiogenesis induced by iloprost and cPGI does not differ in extent and morphology from that induced by VEGF and is associated with local increment of VEGF mRNA expression and protein levels. Finally, iloprost-induced angiogenesis is significantly decreased by systemic inhibition of VEGF activity, obtained by gene transfer of a soluble form of the VEGF receptor Flt-1.
Conclusions. – These data demonstrate that stable PGI₂ analogs may have angiogenic properties in vivo, depending on their ability to act on PPARs. The resulting angiogenic process appears to be mediated by VEGF. These findings indicate that important physiological activities in the cardiovascular system, such as angiogenesis and VEGF induction, may be modulated by PGI₂ through specific activation of the PPAR signaling pathway in vivo, with potentially important fundamental and clinical implications.
Prostacyclins
2013, Handbook of Experimental Pharmacology
Endothelial progenitor cells and angiogenesis join the PPARty
2008, Circulation Research
Prostacyclin therapies for the treatment of pulmonary arterial hypertension
2008, European Respiratory Journal

^f1: Please address all correspondence to: Philip M. Barger, MD, Winters Center for Heart Failure Research, Baylor College of Medicine, MS 524, 6565 Fannin St, Houston, Texas 77030, USA. Tel: (713)441-0421; Fax: (713)441-1252; E-mail:[email protected]

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EditorialHas Angiogenesis Been Invited to the PPARty?

Abstract

Cell

Cell

Cell

J Biol Chem

Trends Cardiovasc Med

J Biol Chem

Prostaglandins Leukot Essent Fatty Acids

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Pharmacol Ther

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Biol Chem

Mol Cell Endo

Peroxisome proliferator-activated receptors: nuclear control of metabolism

Endocr Rev

Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome-proliferator-activted receptors α and δ

Proc Natl Acad Sci USA

Editorial
Has Angiogenesis Been Invited to the PPARty?