IP Receptor-dependent Activation of PPARgamma by Stable Prostacyclin Analogues

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2007 Jul 13

PMID 17624303

Citations 29

Authors

Emilia Falcetti

David M Flavell

Bart Staels

Andrew Tinker

Sheila G Haworth

Lucie H Clapp

Affiliations

Soon will be listed here.

Abstract

Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors (PPARs). So far these agents have been reported to activate PPARalpha and PPARdelta but not PPARgamma. Given PPARgamma agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPARgamma activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPARgamma in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPARgamma antagonist, GW9662. We conclude that PPARgamma is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues.

Citing Articles

Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats.

Corboz M, Nguyen T, Stautberg A, Cipolla D, Perkins W, Chapman R J Aerosol Med Pulm Drug Deliv. 2024; 37(5):241-283.

PMID: 39388691 PMC: 11502635. DOI: 10.1089/jamp.2024.0016.

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog.

Mouratidou C, Pavlidis E, Katsanos G, Kotoulas S, Mouloudi E, Tsoulfas G World J Gastrointest Surg. 2023; 15(9):1858-1870.

PMID: 37901735 PMC: 10600776. DOI: 10.4240/wjgs.v15.i9.1858.

Functional Expression of IP, 5-HT, D, A, and VIP Receptors in Human Odontoblast Cell Line.

Kitayama E, Kimura M, Ouchi T, Furusawa M, Shibukawa Y Biomolecules. 2023; 13(6).

PMID: 37371459 PMC: 10296320. DOI: 10.3390/biom13060879.

Prostaglandin D Added during the Differentiation of 3T3-L1 Cells Suppresses Adipogenesis via Dysfunction of D-Prostanoid Receptor P1 and P2.

Nartey M, Jisaka M, Syeda P, Nishimura K, Shimizu H, Yokota K Life (Basel). 2023; 13(2).

PMID: 36836727 PMC: 9963520. DOI: 10.3390/life13020370.

Arachidonic Acid Added during the Differentiation Phase of 3T3-L1 Cells Exerts Anti-Adipogenic Effect by Reducing the Effects of Pro-Adipogenic Prostaglandins.

Nartey M, Jisaka M, Syeda P, Nishimura K, Shimizu H, Yokota K Life (Basel). 2023; 13(2).

PMID: 36836723 PMC: 9962328. DOI: 10.3390/life13020367.

References

Clark R, Jahangir A, Severance D, Salazar R, Chang T, Chang D . Discovery and SAR development of 2-(phenylamino) imidazolines as prostacyclin receptor antagonists [corrected]. Bioorg Med Chem Lett. 2004; 14(4):1053-6. DOI: 10.1016/j.bmcl.2003.10.070. View

Vane J, Corin R . Prostacyclin: a vascular mediator. Eur J Vasc Endovasc Surg. 2003; 26(6):571-8. DOI: 10.1016/s1078-5884(03)00385-x. View

Hertz R, Berman I, Keppler D . Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR). Eur J Biochem. 1996; 235(1-2):242-7. DOI: 10.1111/j.1432-1033.1996.00242.x. View

Shalev A, Yen P, Wahli W, Burger A, Chin W, Meier C . The peroxisome proliferator-activated receptor alpha is a phosphoprotein: regulation by insulin. Endocrinology. 1996; 137(10):4499-502. DOI: 10.1210/endo.137.10.8828512. View

Zhang B, Berger J, Zhou G, Elbrecht A, Biswas S, Szalkowski D . Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 1996; 271(50):31771-4. DOI: 10.1074/jbc.271.50.31771. View

Forman B, Chen J, Evans R . Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A. 1997; 94(9):4312-7. PMC: 20719. DOI: 10.1073/pnas.94.9.4312. View

Reginato M, Krakow S, Bailey S, Lazar M . Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor gamma. J Biol Chem. 1998; 273(4):1855-8. DOI: 10.1074/jbc.273.4.1855. View

Shao D, Rangwala S, Bailey S, Krakow S, Reginato M, Lazar M . Interdomain communication regulating ligand binding by PPAR-gamma. Nature. 1998; 396(6709):377-80. DOI: 10.1038/24634. View

Gelman L, Zhou G, Fajas L, Raspe E, Fruchart J, Auwerx J . p300 interacts with the N- and C-terminal part of PPARgamma2 in a ligand-independent and -dependent manner, respectively. J Biol Chem. 1999; 274(12):7681-8. DOI: 10.1074/jbc.274.12.7681. View

10.

Turcato S, Clapp L . Effects of the adenylyl cyclase inhibitor SQ22536 on iloprost-induced vasorelaxation and cyclic AMP elevation in isolated guinea-pig aorta. Br J Pharmacol. 1999; 126(4):845-7. PMC: 1571226. DOI: 10.1038/sj.bjp.0702383. View

11.

Juge-Aubry C, Hammar E, PERNIN A, Takeshita A, Chin W, Burger A . Regulation of the transcriptional activity of the peroxisome proliferator-activated receptor alpha by phosphorylation of a ligand-independent trans-activating domain. J Biol Chem. 1999; 274(15):10505-10. DOI: 10.1074/jbc.274.15.10505. View

12.

Giblin J, Leaney J, Tinker A . The molecular assembly of ATP-sensitive potassium channels. Determinants on the pore forming subunit. J Biol Chem. 1999; 274(32):22652-9. DOI: 10.1074/jbc.274.32.22652. View

13.

Narumiya S, Sugimoto Y, Ushikubi F . Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999; 79(4):1193-226. DOI: 10.1152/physrev.1999.79.4.1193. View

14.

Diradourian C, Girard J, Pegorier J . Phosphorylation of PPARs: from molecular characterization to physiological relevance. Biochimie. 2005; 87(1):33-8. DOI: 10.1016/j.biochi.2004.11.010. View

15.

Gelman L, Michalik L, Desvergne B, Wahli W . Kinase signaling cascades that modulate peroxisome proliferator-activated receptors. Curr Opin Cell Biol. 2005; 17(2):216-22. DOI: 10.1016/j.ceb.2005.02.002. View

16.

Chinetti-Gbaguidi G, Fruchart J, Staels B . Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin Pharmacol. 2005; 5(2):177-83. DOI: 10.1016/j.coph.2004.11.004. View

17.

Howard L, Morrell N . New therapeutic agents for pulmonary vascular disease. Paediatr Respir Rev. 2005; 6(4):285-91. DOI: 10.1016/j.prrv.2005.09.006. View

18.

Orie N, Fry C, Clapp L . Evidence that inward rectifier K+ channels mediate relaxation by the PGI2 receptor agonist cicaprost via a cyclic AMP-independent mechanism. Cardiovasc Res. 2005; 69(1):107-15. DOI: 10.1016/j.cardiores.2005.08.004. View

19.

Ali F, Egan K, FitzGerald G, Desvergne B, Wahli W, Bishop-Bailey D . Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts. Am J Respir Cell Mol Biol. 2005; 34(2):242-6. DOI: 10.1165/rcmb.2005-0289OC. View

20.

Bley K, Bhattacharya A, Daniels D, Gever J, Jahangir A, Oyang C . RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol. 2005; 147(3):335-45. PMC: 1751302. DOI: 10.1038/sj.bjp.0706554. View