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Minireview: A Novel Pathway of Prostacyclin Signaling—Hanging Out with Nuclear Receptors

Departments of Obstetrics and Gynecology and Cell Biology and Physiology (H.L.), Washington University School of Medicine, St. Louis, Missouri 63110; and Department of Molecular and Integrative Physiology (S.K.D), Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160

Address all correspondence and requests for reprints to: H. Lim, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110. E-mail: limj{at}msnotes.wustl.edu; or S. K. Dey, Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160. E-mail: sdey{at}kumc.edu.

	Abstract

Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 
Prostacylin (PGI₂), one of the major prostaglandins, is derived from arachidonic acid by the action of the cyclooxygenase (COX) system coupled to PGI₂ synthase (PGIS). The presence of the COX-2/PGIS at the nuclear and endoplasmic reticular membrane suggests differential signaling pathways of PGI₂ actions involving both cell surface and nuclear receptors. Although the signaling of PGI₂ via its cell surface receptor, prostacyclin receptor (IP), is well documented in vascular biology, its action via nuclear receptors in other physiological responses is gradually being more appreciated. Peroxisomal proliferator-activated receptors (PPARs), PPAR, PPAR, and PPAR, though initially cloned as a family of orphan receptors, are now known for their ligand promiscuity. The ligands range from free fatty acids and their derivatives produced by the cyclooxygenase or lipoxygenase pathway to certain hypolipidemic drugs. The predisposition of PPARs to use a wide spectrum of ligands is well explained by their unusually large ligand-binding pocket. The promiscuous ligand usage by PPARs is also reflected by their involvement in various pathophysiological events. Several recent independent reports show that endogenously produced PGI₂ indeed activates PPAR in vivo, indicating that a novel signaling mechanism for this abundant eicosanoid is operative in certain systems. This review attempts to cover recent developments in nuclear actions of PGI₂ in diverse biological functions.

	Introduction

Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 
PROSTACYCLIN (PGI₂) WAS first discovered in 1976 in the course of identifying the generation of unstable eicosanoids in blood vessels. One such novel lipid mediator generated by vascular tissues was characterized as a potent endogenous anticoagulator for platelets and a strong vasodilator (1). This mediator, having opposite physiological behavior of another unstable eicosanoid thromboxane A₂, was the most abundant product of arachidonic acid in vascular tissues and was later named as PGI₂ (2). Like many other lipid mediators of the eicosanoid family derived from arachidonic acid, PGI₂ is produced by the cyclooxygenase (COX) system. Arachidonic acid, first liberated from phospholipid pools by phospholipase A₂, is converted to PGH₂ by COX. PGH₂ is subsequently converted to PGI₂ by the action of PGI₂ synthase (PGIS) (3). On-site production of PGI₂ is executed by either COX-1 or COX-2 coupled to PGIS (4). Whereas PGI₂ is a primary product of COX-2 in certain systems (5, 6, 7), the situation varies depending on the cell types (8). PGI₂ is very labile and undergoes spontaneous transformation to 6-keto-PGF₁ within minutes in vivo (9). Because of its valuable clinical implications in vascular physiology, several synthetic analogs, such as iloprost, cicaprost, and carbarprostacyclin (cPGI) with more stable chemical structures have been developed (10, 11, 12).

	Signaling Mechanisms of PGI2: Prostacyclin Receptor (IP) and Peroxisome Proliferator-Activated Receptors (PPARs)

Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 
Both COX and PGIS have been shown to be localized at nuclear and endoplasmic reticular membranes (8, 13, 14, 15, 16), suggesting that dual signaling pathways, one using exported PGs from endoplasmic reticulum and the other using nuclear PGs, exist in certain cell types. The classical signaling pathway of PGI₂ uses a G protein-coupled cell surface receptor termed IP (17). Activation of IP by an agonist leads to increased production of intracellular cAMP via stimulation of adenylyl cyclase. Heightened levels of intracellular cAMP in turn activates protein kinase A cascade, or calcium mobilization via phospholipase C activation (17, 18). Vascular tissues, both endothelial and underlying smooth muscle cells, have the capacity to generate PGI₂ via PGIS. PGI₂ acts upon vascular tissues and platelets as a potent vasodilator and anticoagulator (9), and these characteristics are mimicked by various PGI₂ agonists (19, 20). Studies using IP-deficient mice also provided insightful evidence that PGI₂-IP signaling is indeed important in preventing thrombosis in vivo and that it is involved in inflammatory responses (21).

Differential subcellular localization of PG synthesizing machinery began to make more sense when a class of nuclear receptors known as PPARs was shown to use a broad spectrum of lipid mediators and synthetic drugs as ligands for transcriptional activation (22, 23, 24, 25). PPARs belong to a family of ligand-activated transcription factors and heterodimerization with a retinoid X receptor is a prerequisite for their DNA binding activity (26) and recruitment of transcriptional cofactors is required to activate target genes (27). Along with several synthetic ligands including specific hypolipidemic drugs, certain eicosanoids and fatty acids were identified as PPAR ligands. For example, PGI₂ agonists such as cPGI and iloprost can effectively induce DNA binding and transcriptional activation by PPAR and PPAR. Interestingly, unlike other PGI₂ agonists, cicaprost is incapable of inducing dimerization between PPAR or PPAR and retinoid X receptor (24). PGI₂ itself also failed to induce dimerization under these experimental conditions, possibly because the chemical instability of this PG precluded it to reach the nuclear target. Alternatively, whereas cell-permeable cPGI makes its way into the nucleus more efficiently, a specific PG transporter may be required for intracellular delivery of PGI₂. Leukotriene B₄, a product of arachidonic acid generated by the lipoxygenase pathway, was reported as a PPAR ligand as well (28). As for PPAR, 15-deoxy-^12,14-PGJ₂, a PGD₂ metabolite, was first proposed as a ligand in an adipocyte differentiation model (29, 30). Because of the important role of PPAR and PPAR in metabolic diseases (reviewed in Ref. 31), many synthetic ligands of PPARs are being continuously developed. However, the question of endogenous ligand utilization by these receptors remains mostly unanswered. Nevertheless, recent work using diverse systems show that PPAR in fact uses PGI₂ as an endogenous ligand to modulate specific cellular functions.

	PGI2 as a Ligand for PPAR

Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 
Embryo implantation
PGI₂ is the most abundant PG in the early pregnant mouse uterus and is especially higher at implantation sites than in interimplantation sites (32, 33). Consistent with the finding that COX-2 driven uterine PG production is crucial to implantation (34), COX-2 and PGIS coexist at the implantation site, suggesting the availability of PGI₂ directly to uterine cells. In searching for a target receptor for PGI₂ in the uterus, the expression of known PGI₂ receptors, such as IP, PPAR, and PPAR, was examined. Among these, PPAR was shown highly colocalized at similar regions of the implantation sites with COX-2 and PGIS; the expression of IP and PPAR was very low to undetectable. The functionality of PPAR as a PGI₂ receptor was further validated in vivo, using COX-2-deficient mice as a model. Administration of cPGI or L-165041 (a selective PPAR agonist) improved implantation and decidualization defects in COX-2(-/-) mice (33). Along with other in vitro evidence, this work demonstrated that maternal PPAR expressed in the uterine stroma actively responds to a PGI₂ agonist to mediate embryo implantation. However, cicaprost, an IP agonist but with no PPAR agonism, had no effect.

Colorectal cancer
COX-2 is overexpressed in colorectal cancers in humans and animals, and COX-2-derived PGs modulate angiogenesis and cell adhesion during tumorigenesis (35, 36). Recent evidence shows that PPAR is also overexpressed in colorectal cancers and its expression is colocalized with COX-2 within the tumor (37, 38). Furthermore, a recent in vitro study demonstrated that endogenous production of PGI₂ by coexpression of COX-2 and PGIS indeed leads to transcriptional activation of PPAR, whereas coexpression of COX-1 and PGIS failed to generate any significant level of PGI₂ and transcriptional activation of PPAR (38). These results clearly indicate that coupling of COX-2 and PGIS leads to impressive production of PGI₂ within a cell and that endogenously produced PGI₂ in fact uses PPAR as its receptor. It is interesting to note that co-overexpression of COX-2 and PPAR has also been reported in endometrial adenocarcinoma (39). Although the mechanism by which COX-2-PPAR pathway promotes neoplastic transformations in certain tissues warrants further investigation, there is evidence that PPAR is involved in vascular functions (see below).

Vascular functions
PGI₂ is unequivocally one of the most abundant PGs in vasculature (1). Classic experiments using isolated platelets and blood vessels in vitro demonstrated that different PGI₂ agonists exhibit anticoagulation and vasodilating activities (10, 19, 20). Although the anticoagulating activity of PGI₂ seems to be mediated primarily by IP (21), its effects on vasculature may be shared between IP and PPAR. Accumulating evidence supports this assumption. Increased endometrial vascular permeability and angiogenesis at the site of embryo are hallmarks of implantation and decidualization. Using a variety of proangiogenic markers, we have recently observed that cPGI or PPAR agonists can improve implantation defects in COX-2-deficient mice with improved angiogenesis at the implantation site (unpublished observation). Furthermore, PPAR is expressed in vascular smooth muscle cells and promotes their proliferation (40). These results suggest a role for PPAR in vascular biology and also propose an interesting paradigm that a single ligand provokes two distinct signaling pathways, i.e. via a cell surface receptor and a nuclear receptor. However, the time course of these two signaling mechanisms could be different, further elucidation of which may establish a correlation between these two different pathways.

Apoptosis
Endogenously produced PGI₂ apparently uses PPAR to modulate apoptotic process as well (41). In this report, the authors show that endogenous production of PGI₂ activates endogenously expressed PPAR in a kidney cell line, leading to an apoptotic response. It is interesting to note that addition of exogenous PGI₂ or cAMP-elevating agents showed opposing effects. These results are suggestive of possible cross-talk between PPAR and certain cytoplasmic signaling pathways. On a similar note, PPAR is associated with keratinocyte differentiation in response to inflammatory stimuli and activated PPAR in the skin seems to regulate genes associated with apoptosis (42). Although this work suggested that an endogenously produced PPAR ligand is required for PPAR activation following inflammatory stimuli, the identity of this putative ligand remains unknown.

	Studies on PPAR-Deficient Mice: Tales of Diversity

Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 
Three reports on PPAR-deficient mice show multiple functions of this previously neglected member of the PPAR family, although the variable phenotypes observed could be due to different genetic backgrounds of mice used in these studies. Peters and collaborators reported that PPAR(-/-) mice were born below the expected Mendelian ratio and were smaller than their littermates (43). Although certain developmental defects were implicated in this finding, the cause of embryonic lethality in a subset of PPAR null fetuses was not delineated. These mutant mice had smaller gonadal fat stores contributing to smaller body weights, and they also exhibited altered myelination in the central nervous system, suggesting an alteration in fatty acid metabolism. Whether the surviving PPAR(-/-) mice were fertile was not reported. In another study, more than 90% of PPAR(-/-) embryos showed severe developmental defects primarily due to placental malformation (44). Therefore, only a handful of PPAR(-/-) mice on a specific genetic background escaped from the placental defects and survived to adulthood. The very few surviving PPAR(-/-) mice showed reduced adiposity and were stated to have no apparent fertility defects. In contrast, another group has reported that the majority of the PPAR(-/-) embryos die in utero or failed to survive to adulthood due to yet to be identified developmental defects, and a surviving line has variable and often reduced fertility (Ref. 45 ; and Desvergne, B., and W. Wahli, personal communication). Therefore, the characterization of reproductive phenotypes in the absence of PPAR will require in-depth study using mice on different genetic backgrounds. The skin of PPAR(-/-) mice also displays an increased hyperplasic response to an inflammatory response (43, 45), possibly by regulating apoptotic signaling (45). Although these reports show broad action of PPAR in developmental and metabolic processes, specific ligand usage by PPAR, whether it is PGI₂ or other endogenous ligands, in different tissues requires further investigation.

	Sophisticated Signaling Network of PGI2—To Be Untangled

Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 
The handful of evidence showing the role of PPAR as a PGI₂ receptor is a good starting point to gain deeper insights into the mechanism of nuclear PGs. Although PPAR is also known to interact with PGI₂ agonists (24), no further studies are yet reported. Because of the promiscuity of ligand recognition by PPAR, its activation in vivo or in vitro does not always involve PGI₂. As mentioned, due to a large cavity in the ligand binding domain (25), PPARs can also be activated by polyunsaturated fatty acids, such as linoleic acid and arachidonic acid, and by certain classes of synthetic drugs. Studies on the interaction of PPAR and these ligands are more focused on lipid biology. For example, several reports illustrate that fatty acids modulate proliferation and differentiation of adipocyte via PPAR in vitro (46, 47, 48). Moreover, studies using PPAR-selective synthetic agonists suggest a role for this receptor in lipid metabolism (49, 50), although which natural ligands of PPAR would serve as an endogenous counterpart for this action is still unknown. It is therefore possible that differential ligand usage by one receptor may lead to completely different physiological outcomes depending on the cellular context.

Although this scheme of differential ligand usage adopted by PPARs may explain wide range of their functions, dissection of PPAR signaling pathway may shed light on understanding the convergence of intracellular signaling pathways activated by a single ligand. IP, the classical cell-surface receptor for PGI₂, is known to mediate increases in intracellular cAMP production. Interestingly, there is evidence that cAMP signaling pathway modulates PPAR function, possibly by transactivation (51, 52). Especially in the model of adipocyte differentiation, both IP and PPAR are expressed and responsive to cPGI (52, 53). This appears to be an excellent system to untangle a possible mechanism of signal integration and diversification of PGI₂ in and out of the nucleus. Further investigation on the endogenous ligand usage by PPAR in different cellular systems will also help elucidate the physiological importance of the ligand promiscuity displayed by the receptor.

	Acknowledgments

 
We thank Rajnish Gupta (Vanderbilt University Medical Center) for critical reading of the manuscript.

	Footnotes

 
This work was supported by NIH Grants HD-12304, HD-29968, and HD-33994 (awarded to S.K.D.) and HD-40810 (awarded to H.L.). S.K.D. is a recipient of an NICHD MERIT award.

Abbreviations: cPGI, Carbarprostacyclin; COX, cyclooxygenase; IP, prostacyclin receptor; PG, prostaglandin; PGI₂, prostacylin; PGIS, PGI₂ synthase; PPAR, peroxisome proliferator-activated receptors.

Received February 8, 2002.

Accepted for publication March 22, 2002.

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Top Abstract Introduction Signaling Mechanisms of PGI2:... PGI2 as a Ligand... Studies on PPAR{delta}-Deficient... Sophisticated Signaling Network... References

 

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