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Review Article published: 14 October 2010 doi: 10.3389/fphar.2010.00116

PG F2α : a promising therapeutic target for cardiovascular disease

Jian Zhang, Yanjun Gong and Ying Yu*

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

Edited by: (PGs), a group of key lipid mediators, are involved in numerous physiological Colin D. Funk, Queen’s University, and pathological processes including inflammation and cardiovascular homeostasis. Each PG Canada acts on its specific and distinct cell surface -coupled receptors (GPCRs) or peroxisome Reviewed by: proliferator-activated receptors (PPARs). F receptor (FP) is required for female Aida Habib, American University of 2α Beirut, Lebanon reproductive function such as luteolysis and parturition. It has recently been implicated in blood Duxin Sun, University of Michigan, pressure regulation, atherosclerosis and other inflammation-related disorders. The emerging USA role of FP in cardiovascular diseases is highlighted and potential therapeutic is *Correspondence: discussed in the current review. Ying Yu, Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Keywords: , hypertension, atherosclerosis, FP receptor Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 294 Tai Yuan Road, Shanghai 200031, China. email: [email protected]

Introduction through peroxidase activity (POX) of PGHS . Subsequently

Prostanoids, including prostaglandin (PG) E2, PGD2, prostacy- the PGH2 is subject to metabolize to active through clin (PGI2), (TxA2), and PGF2α, are generated individual PG synthases (Figure 1). Diversity in expression of through PGH synthase (PGHS) – known commonly as cyclooxy- downstream synthases results in the generation of one or two genase (COX), in response to a wide variety of stimuli acting as dominant PGs by individual cells. In general, PGF2α is formed by paracrine or autocrine manner. Non-steroidal anti-inflammatory reduction of PGH2 by PG endoperoxide synthase or reductase. It drugs (NSAIDs) such as , , inhibit COX isforms also can be also formed from other PGs (Figure 1) such as PGE2 to achieve antipyretic, analgesic, and anti-inflammatory actions through 9-keto reductases and PGD2 through 11-keto reductases through blocking PGs biosynthesis (Funk, 2001). Accumulating (Watanabe et al., 1985), although relatively rare. Endogenous pri- evidences demonstrate COX-derived PGs play crucial role in mary PGF2α is rapidly degraded enzymatically, half-life is less than mediating an array of cellular processes such as cell proliferation, 1 min in peripheral circulation, and its relatively stable metabolite differentiation, and apoptosis and in regulating female reproduc- is 15-keto-dihydro-PGF2α (Basu et al., 1992). tive function and parturition, platelet aggregation, and vascular PGF2α exits in almost all the tissues (Basu, 2007) with more abun- homeostasis (Smith et al., 2000; Yu et al., 2006; Funk and FitzGerald, dant in the female reproductive system (Hao and Breyer, 2008); 2007; Yu and Funk, 2007). In addition, PGs also are involved in its cellular and physiological effects are mediated by a G protein- pathogenesis of inflammation, cancer, and cardiovascular disorders coupled receptor-the F receptor (the FP; Narumiya et al.,

(FitzGerald and Loll, 2001; Smyth et al., 2009). The biological func- 1999). Two splice forms of FP (FPA and FPB) exist in human. Initially, tions of PGs could be modulated at multiple levels such as COX, PG the FP receptor was characterized as coupling to Gq protein which synthases, and downstream receptors (Narumiya and FitzGerald, lead to inositol triphosphate (IP3)/diacylglycerol (DAG) genera- 2001). Elucidating the physiological roles of COX-derived PGs in tion and mobilization of intracellular calcium (Abramovitz et al., cellular and whole body homeostasis and the mechanism under- 1994; Sugimoto et al., 1994; Watanabe et al., 1994), which is linked lying their action will no doubt offer opportunity for developing to the proliferation of cells (Watanabe et al., 1994). Stimulation of novel therapeutics for inflammatory disease, cancer, and hyperten- FP also led to activation of the small G protein Rho, resulting in sion. Here, we summarized the recent works focusing on PGF2α/FP phosphorylation of the p125 focal adhesion kinase, cytoskeleton receptor response in cardiovascular system and reviewed the recent rearrangement and cell morphology change (Pierce et al., 1999), development of potential therapeutic target of FP receptor. and -mediated phosphorylation of the receptor (EGFR) and mitogen-activated protein kinase

PGF2α and FP receptor (MAPK) signaling pathways in endometrial adenocarcinoma cells Prostanoids are formed through COXs on via a (Sales et al., 2004). Recently, the coupling of Gi of FP receptor has two-step enzymatic process. First the arachidonic acid is biocon- been reported, which is response for water reabsorption in renal verted to PGG2 through COX catalytic activity and then PGH2 collecting ducts in rabbit (Hebert et al., 2005).

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Figure 1 | Prostanoid biosynthesis and response pathway. AA, arachidonic prostaglandin F synthase; PGDS, synthase; TxS, thromboxane

acid; PLA2, phospholipase A2; PGHS1/2, prostaglandin G/H synthase 1 or 2, A2 synthase; IP, prostaglandin I2 receptor; EP, receptor; FP,

which contains both cyclooxygenases (COX) and peroxidase (POX) activities; prostaglandin F2α receptor; DP, prostaglandin D2 receptor; TP, thromboxane A2

PGIS, prostaglandin I2 synthase; PGES, prostaglandin E2 synthase; PGFS, receptor.

Expression of FP receptor and its corresponding function are FP in cardiovascular diseases summarized in Table 1. FP is highly expressed in the genitourinary In the heart, PGF2α derives mainly from cardiac fibroblasts and its tract (Sugimoto et al., 1997; Saito et al., 2003). manipulation formation is increased in endocardium by ischemia (Rabinowitz studies showed that, parturition is disrupted in mice lacking either et al., 1992), where it depresses contractile recovery through a cytosolic phospholipase A2 (cPLA2; Bonventre et al., 1997), that mechanism associated with altered cellular energy metabolism mobilizes arachidonic acid release for COX metabolism, COX-2, and increased calcium accumulation (Karmazyn et al., 1993). the more regulated form of that (Dinchuk et al., 1995; Through FP receptor, PGF2α promotes expression of c-fos, atrial Morham et al., 1995) or the FP receptor (Sugimoto et al., 1997). natriuretic factor (ANF), and alpha-skeletal actin in cardiomyo- Likewise, the onset of parturition is delayed in COX-1 knock out cytes and induces cardiac myocyte hypertrophy in vitro and car- (KO) mice (Langenbach et al., 1995) but not COX-1 knockdown diac growth in rat (Lai et al., 1996), but does not affect myocyte (KD; Yu et al., 2005). This results in high neonatal mortality that proliferation in culture (Adams et al., 1996). Mechanistic studies 2+ can be rescued by PGF2α replacement (Gross et al., 1998). In the eye, showed PGF2α inhibits expression Ca -ATPase (SERCA2) via the FP is expressed in the vasculature, the iris sphincter and in the induction of Early Growth Response Protein 1 (Egr-1) in cultured anterior circular muscles, all relevant to the increased uveoscleral neonatal cardiac myocytes (Hara et al., 2008). We have recently outflow of aqueous humor provoked by PGF2α (Mukhopadhyay found that selective deletion of cardiomyocyte COX-2 releases et al., 2001). FP are approved for local application in the a restraint on expression of fibroblast COX-2, thereby augment- treatment of (Ishida et al., 2006). Recently, abundant FP ing PGF2α formation. This, in turn, coincides with an increase expression has also been detected in the distal convoluted tubules in myocardial fibrosis and a predisposition to arrhythmogenesis

(DCT) and cortical collecting ducts (CCD) of the kidney (Saito (Wang et al., 2009). COX-2 derived PGF2α can further promote et al., 2003), implicating its role in water and electrolyte homeos- fibroblast PGF2α formation in a feed forward manner (Yoshida tasis (Hebert et al., 2005). FP is observed in lung tissue and lung et al., 2002) and progressively promote fibrosis (Almirza et al., fibroblasts, which facilitates -induced pulmonary fibrosis 2008). PGF2α promotes arrhythmias in cultured neonatal rat car- independently of transforming growth factor β (TGFβ; Oga et al., diac myocytes (Kunapuli et al., 1997; Li et al., 1997) and FP dele- 2009). No FP receptor seems been detected in immune system tion protects against inflammatory tachycardia in mice in vivo organs such as spleen and thymus (Tilley et al., 2001). (Takayama et al., 2005). Thus, PGF2α/FP response is involved in

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multiple aspects of ischemia heart disease (Figure 2), blockage of Vascular endothelial cells secrete surprisingly large amounts the FP may facilitate recovery from cardiac ischemia-reperfusion of PGF2α in response to shear stress in vitro (Di Francesco et al., induced injury. 2009). The relevance of this phenomenon is poorly understood

Table 1 | FP expression and its physiological/pathological function.

Tissue/cell distribution Physiological/pathological process References Ovary Luteolysis, parturition Sugimoto et al. (1997), Gross et al. (1998), Saito et al. (2003) Myometrium Uterine contraction Brodt-Eppley and Myatt (1999), Fischer et al. (2008) Ocular vasculature; iris sphincter; ocular Aqueous humor homeostasis Mukhopadhyay et al. (2001) circular muscles Renal distal convoluted tubule, cortical Water and electrolyte reabsorption Saito et al. (2003), Hebert et al. (2005), Hao and Breyer collecting duct (2008) Juxtaglomerular apparatus secretion; regulation Yu et al. (2009) Lung fibroblast Pulmonary fibrosis Oga et al. (2009) Cardiac fibroblast; cardiomyocyte Myocardial fibrosis; arrhythmias; myocyte Lai et al. (1996), Kunapuli et al. (1997), Li et al. (1997), hypertrophy Yoshida et al. (2002), Takayama et al. (2005), Almirza et al. (2008), Wang et al. (2009) Vascular smooth muscle cell (VSMC) VSMC hypertrophy; vasoconstriction Whittle et al. (1985b), Rice et al. (2008), Yu et al. (2009)

Figure 2 | Scheme of PGF2α/FP pathway involved in pathogenesis of through enhancing salt/water reabsorption in kidney and constricting blood

cardiovascular disease. Cardiac fibroblasts derived PGF2α induces cardiac vessels directly via II (Ang II); PGF2α promotes resistance artery hypertrophy, fibrosis and arrhythmia through FP receptor in adjacent constriction through FP in smooth muscle cells (SMCs), which eventually

cardiomyocytes (CMs); PGF2α stimulates renin release from juxtaglomerular increases blood pressure and contributes to atherosclerosis; Activated RAAS granular cells (JGCs) by FP receptor in an autocrine fashion, and activate also accelerates atherosclerosis. JGA, juxtaglomerular apparatus; AGT, renin–angiotensin–aldosterone system (RAAS) to elevate blood pressure angiotensinogen; ACE, angiotensin-converting enzyme; ALD, aldosterone.

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but in sufficient quantities. PGF2α may act as an incidental associated with those increased cardiovascular risk, such as smoking at the TxA2 receptor-the TP (Wong et al., 2009). Furthermore, the (Helmersson et al., 2005a), obese (Sinaiko et al., 2005), rheumatic expression of FP receptors in the medial layer of resistance vessels disease (Basu et al., 2001), type I (Basu et al., 2005) and type II was observed (Yu et al., 2009), which is involved in vasoconstric- (Helmersson et al., 2004) diabetes mellitus; increased PGF2α was tion (Whittle et al., 1985a). Thus it might prove relevant to the found in urine from population with hypercholesterolemia and regulation of systemic blood pressure (BP) as PGF2α direct infu- smoking – the conditions associated with oxidative stress (Yin sion causes dose-dependent elevation of BP in anesthetized mice et al., 2007). Moreover, plasma PGF2α level in the elder man is posi-

(Yu et al., 2009). Moreover, PGF2α increases reactive oxygen species tively related with common carotid artery intima-media thickness (ROS) and induces vascular smooth muscle cells (VSMCs) hyper- (CCA-IMT) (Wohlin et al., 2007) – a valid index of atherosclerosis. trophy through translocation of mammalian target of rapamycin Moreover, a polymorphism in COX-1 gene (rs10306135) identi-

(mTOR) from nucleus to cytoplasm and activation of phosphati- fied recently is associated with significantly decreased PGF2α and dylinositol 3-kinase (PI3K) pathway (Rice et al., 2008). In mice, further lower susceptibility for cardiovascular disease (Helmersson

FP deletion reduces significantly BP in mice, both when they are et al., 2009). Hence, PGF2α maybe involved in initiation and pro- placed on a regular chow diet and after manipulation of dietary gression of chronic cardiovascular diseases, such as atherosclerosis fat or sodium intake. This coincides with decreased activation of and hypertension. renin–angiotensin–aldosterone system (RAAS; Yu et al., 2009). FP receptor expression is marked in afferent arterioles of the juxta- Pharmacology of FP modulation glomerular apparatus (JGA) and renin-containing granular cells Given the accumulating evidence pleading for the involvement of −/− are decreased in the FP deficient mice (FP ). Indeed, activation PGF2α/FP receptor response pathway in regulating ocular uveo- of the FP appears to regulate juxtaglomerular (JG) cell differen- scleral outflow and normal parturition as well as pathogenesis of tiation and consequent renin expression, explaining depressed hypertension and atherosclerosis, the exploration of novel com- activation of the RAAS in FP−/− mice. Although FP expression pounds able to specifically stimulate or inhibit FP receptor will was not detected in the aorta or even when it was complicated constitute promising therapeutic avenues. by atherosclerotic lesions, FP deletion attenuates atherogenesis Human FP receptors are expressed in the human ocular in hyperlipidemic mice [low-density lipoprotein (LDL) receptor (Anthony et al., 1998) and topical exog- −/− knockout, Ldlr ]. Perhaps restraint of atherogenesis in Ldlr/FP enous PGF2α and FP agonists reduce intraocular pressure (IOP) double knockout (Ldlr−/−/FP−/−) mice merely results from dis- in monkeys and humans without causing inflammation (Weinreb ruption of renal RAAS activation with a consequent impact on et al., 2002). Thus, FP agonists, , , and systemic BP (Figure 2). Taken together, antagonism of the FP , are used in the treatment of glaucoma and ocular receptor may afford a strategy for the control of hypertension hypertension (Ishida et al., 2006), although the precise mechanism and its attendant vascular diseases such as atherosclerosis (Yu by which they work is poorly understood. More directly relevant et al., 2009). has been the suggestion that FP antagonism may delay luteoly- sis and uterine contraction during parturition (Bernal, 2001),

PGF2α in human inflammatory disease with the potential to delay preterm birth (Olson, 2005). Until

In human studies, PGF2α is one of the more abundant PGs recently, AL-8810, reported 10 years ago, is the first described FP formed at sites of inflammation (Scher and Pillinger, 2009), antagonist, albeit that it is a partial (Griffin et al., 1999) and is subject to inhibition by NSAIDs such as low dose aspirin with which there is much experience in model systems (Sharif

(Helmersson et al., 2005b). Similar to PGE2, PGF2α is present in et al., 2000; Hirst et al., 2005). Theratechnologies compound THG joint fluid collected from , psoriatic arthri- 113 tested as FP receptor blocker, inhibits the contractile activ- tis, osteoarthritis patients (Trang et al., 1977; Basu et al., 2001), ity of smooth muscle cells from mouse (Peri et al., 2002), sheep and the levels of these PGs could also be effectively retarded by (Hirst et al., 2005), and human myometrium (Friel et al., 2005)

NSAIDs treatment. In addition, the synovial cells from rheuma- in response to exogenous PGF2α in vitro probably through activat- 2+ + toid arthritis patient are able to secrete PGF2α in vitro (Seppala, ing Ca -activated K channel (BKCa; Doheny et al., 2007), and

1987). Along with 8-Iso-PGF2α-oxidative stress marker, PGF2α delays lipopolysaccharide (LPS)-induced preterm birth in mice was elevated during the first hour in acute myocardial infarction (Peri et al., 2002), and lowers uterine electromyographic activity (AMI) patient treated with percutaneous coronary intervention and delays RU486 (a receptor blocker)-induced pre- (PCI; Berg et al., 2005) and 24 h after post-surgery in elective term birth in sheep (Hirst et al., 2005). More recently, AS604872, PCI patients probably due to aspirin treatment before operation another patented FP antagonist, was shown to be effective to delay (Berg et al., 2004). preterm parturition in rodents (Chollet et al., 2007; Cirillo et al., Atherosclerosis is a chronic vascular inflammation diseases 2007). Thus, FP receptor could be a potential target for the phar- characterized by the thickening of the arterial wall (Rader and macological management of preterm labor. Given that renin is

Daugherty, 2008). Vascular endothelial dysfunction is believed as elevated in pregnancy-induced hypertension with decreased PGI2 initial step during atherogenesis, high plasma LDL, free oxygen biosynthesis (Fitzgerald et al., 1987), FP antagonist seems more radicals caused by cigarette smoking, hypertension, and diabetes suitable theoretically for management of pregnancy-induced mellitus, and other genetic defects could cause endothelial dysfunc- hypertension with broad gestational benefits. However, further tion leading to atherosclerosis (Ross, 1999). As the major metabo- clinical investigation is required regarding therapeutic efficacy of lite of PGF2α, 15-keto-dihydro-PGF2α is elevated in the conditions FP antagonist in clinic.

Frontiers in Pharmacology | Inflammation Pharmacology October 2010 | Volume 1 | Article 116 | 4 Zhang et al. FP and cardiovascular disease

Conclusion Given the use of FP agonists in the treatment of glaucoma, the

In summary, PGF2α, an early focus of prostaglandin research has ­synthesis of antagonists seems readily tractable. Such pharma- been quite neglected outside the field of reproductive biology in cological probes will facilitate our determination of whether FP recent decades. However, emerging evidence, particularly from antagonists might have utility in a wide variety of cardiovascular mice lacking its FP receptor, hint at its importance in BP regu- disorders in the future. lation and atherosclerosis. PGI2 is a potent renin secretagogue, antagonism or deletion of its receptor (the IP) protects against Acknowledgments high-renin hypertension in renoprival models of in rodents This work was supported by grants from Chinese Academy of (Fujino et al., 2004), while accelerates atherogenesis (Kobayashi Sciences (Knowledge Innovation Program O914X41281 and Talent et al., 2004). Thus, blockade of the FP may represent a novel 100 Program 2010OHTP10), Clinic Research Center at Institute therapeutic strategy in syndromes of renin dependent hyper- for Nutritional Sciences, Shanghai Institutes for Biological Sciences tension with a more cardioprotective profile than suppressing (CRC2010007) and the Ministry of Science and Technology of synthesis or disrupting activation of the PGI2 receptor (IP). China (2011CB503906).

References response during and following coro- Dinchuk, J. E., Car, B. D., Focht, R. J., Funk, C. D., and FitzGerald, G. A. (2007). Abramovitz, M., Boie, Y., Nguyen, T., nary interventions for acute myocar- Johnston, J. J., Jaffee, B. D., Covington, COX-2 inhibitors and cardiovascular Rushmore, T. H., Bayne, M. A., dial infarction. Free Radic. Res. 39, M. B., Contel, N. R., Eng, V. M., Collins, risk. J. Cardiovasc. Pharmacol. 50, Metters, K. M., Slipetz, D. M., and 629–636. R. J., Czerniak, P. M., Gorry, S. A, and 470–479. Grygorczyk, R. (1994). Cloning and Berg, K., Wiseth, R., Bjerve, K., Brurok, Trzaskos, J. M. (1995). Renal abnor- Griffin, B. W., Klimko, P., Crider, J. Y., expression of a cDNA for the human H., Gunnes, S., Skarra, S., Jynge, P., and malities and an altered inflammatory and Sharif, N. A. (1999). AL-8810: a prostanoid FP receptor. J. Biol. Chem. Basu, S. (2004). Oxidative stress and response in mice lacking cyclooxyge- novel prostaglandin F2 alpha analog 269, 2632–2636. myocardial damage during elective nase II. Nature 378, 406–409. with selective antagonist effects at the Adams, J. W., Migita, D. S., Yu, M. K., percutaneous coronary interventions Doheny, H. C., O’Reilly, M. J., Sexton, D. J., prostaglandin F2 alpha (FP) recep- Young, R., Hellickson, M. S., Castro- and coronary angiography. A com- and Morrison, J. J. (2007). THG113.31, tor. J. Pharmacol. Exp. Ther. 290, Vargas, F. E., Domingo, J. D., Lee, P. parison of blood-borne isoprostane a specific PGF2alpha receptor antago- 1278–1284. H., Bui, J. S., and Henderson, S. A. and troponin release. Free Radic. Res. nist, induces human myometrial relax- Gross, G. A., Imamura, T., Luedke, C., (1996). Prostaglandin F2 alpha stimu- 38, 517–525. ation and BKCa channel activation. Vogt, S. K., Olson, L. M., Nelson, D. M., lates hypertrophic growth of cultured Bernal, A. L. (2001). Overview of current Reprod. Biol. Endocrinol. 5, 10. Sadovsky, Y., and Muglia, L. J. (1998). neonatal rat ventricular myocytes. J. research in parturition. Exp. Physiol. Fischer, D. P., Hutchinson, J. A., Farrar, Opposing actions of prostaglandins Biol. Chem. 271, 1179–1186. 86, 213–222. D., O’Donovan, P. J., Woodward, and determine the onset of Almirza, W. H., Dernison, M. M., Peters, Bonventre, J. V., Huang, Z., Taheri, M. R., D. F., and Marshall, K. M. (2008). murine labor. Proc. Natl. Acad. Sci. P. H., van Zoelen, E. J., and Theuvenet, O’Leary, E., Li, E., Moskowitz, M. A., Loss of prostaglandin F2alpha, but U.S.A. 95, 11875–11879. A. P. (2008). Role of the prostanoid FP and Sapirstein, A. (1997). Reduced fer- not thromboxane, responsiveness Hao, C. M., and Breyer, M. D. (2008). receptor in action potential generation tility and postischaemic brain injury in in pregnant human myometrium Physiological regulation of pros- and phenotypic transformation of NRK mice deficient in cytosolic phospholi- during labour. J. Endocrinol. 197, taglandins in the kidney. Annu. Rev. fibroblasts.Cell. Signal. 20, 2022–2029. pase A2. Nature 390, 622–625. 171–179. Physiol. 70, 357–377. Anthony, T. L., Pierce, K. L., Stamer, W. D., Brodt-Eppley, J., and Myatt, L. (1999). Fitzgerald, D. J., Entman, S. S., Mulloy, Hara, S., Arai, M., Tomaru, K., Doi, H., and Regan, J. W. (1998). Prostaglandin Prostaglandin receptors in lower seg- K., and FitzGerald, G. A. (1987). Koitabashi, N., Iso, T., Watanabe, F2 alpha receptors in the human ment myometrium during gestation Decreased biosynthesis A., Tanaka, T., Maeno, T., Suga, T., trabecular meshwork. Invest. and labor. Obstet. Gynecol. 93, 89–93. preceding the clinical manifestation Yokoyama, T., and Kurabayashi, M. Ophthalmol. Vis. Sci. 39, 315–321. Chollet, A., Tos, E. G., and Cirillo, R. of pregnancy-induced hypertension. (2008). Prostaglandin F2alpha inhibits Basu, S. (2007). Novel cyclooxygenase- (2007). Tocolytic effect of a selective Circulation 75, 956–963. SERCA2 gene transcription through catalyzed bioactive prostaglandin FP in rodent mod- FitzGerald, G. A., and Loll, P. (2001). an induction of Egr-1 in cultured neo- F2alpha from physiology to new prin- els reveals an innovative approach to COX in a crystal ball: current sta- natal rat cardiac myocytes. Int. Heart ciples in inflammation. Med. Res. Rev. the treatment of preterm labor. BMC tus and future promise of prostag- J. 49, 329–342. 27, 435–468. Pregnancy Childbirth 7(Suppl. 1), landin research. J. Clin. Invest. 107, Hebert, R. L., Carmosino, M., Saito, Basu, S., Larsson, A., Vessby, J., Vessby, B., S16. 1335–1337. O., Yang, G., Jackson, C. A., Qi, Z., and Berne, C. (2005). Type 1 diabetes Cirillo, R., Tos, E. G., Page, P., Missotten, M., Friel, A. M., O’Reilly, M. W., Sexton, D. Breyer, R. M., Natarajan, C., Hata, A. is associated with increased cycloox- Quattropani, A., Scheer, A., Schwarz, J., and Morrison, J. J. (2005). Specific N., Zhang, Y., Guan, Y., and Breyer, M. ygenase- and cytokine-­mediated M. K., and Chollet, A. (2007). Arrest PGF(2alpha) receptor (FP) antago- D. (2005). Characterization of a rab- inflammation. Diabetes Care 28, of preterm labor in rat and mouse nism and human uterine contractility bit kidney prostaglandin F(2{alpha}) 1371–1375. by an oral and selective nonprosta- in vitro. BJOG 112, 1034–1042. receptor exhibiting G(i)-restricted sig- Basu, S., Sjoquist, B., Resul, B., and noid antagonist of the prostaglandin Fujino, T., Nakagawa, N., Yuhki, K., naling that inhibits water absorption Stjernschantz, J. (1992). Presence F2alpha receptor (FP). Am. J. Obstet. Hara, A., Yamada, T., Takayama, K., in the collecting duct. J. Biol. Chem. of a 15-ketoprostaglandin delta 13--­ Gynecol. 197, 54.e 1–e9. Kuriyama, S., Hosoki, Y., Takahata, 280, 35028–35037. reductase in porcine cornea. Acta Di Francesco, L., Totani, L., Dovizio, M., O., Taniguchi, T., Fukuzawa, J., Helmersson, J., Arnlov, J., Axelsson, T., and Chem. Scand. 46, 108–110. Piccoli, A., Di Francesco, A., Salvatore, Hasebe, N., Kikuchi, K., Narumiya, Basu, S. (2009). A polymorphism in Basu, S., Whiteman, M., Mattey, D. L., and T., Pandolfi, A., Evangelista, V., S., and Ushikubi, F. (2004). Decreased the cyclooxygenase 1 gene is associ- Halliwell, B. (2001). Raised levels of Dercho, R. A., Seta, F., and Patrignani, susceptibility to renovascular hyper- ated with decreased inflammatory F(2)-isoprostanes and prostaglandin P. (2009). Induction of prostacyclin tension in mice lacking the prostag- prostaglandin F2alpha formation and F(2alpha) in different rheumatic dis- by steady laminar shear stress sup- landin I2 receptor IP. J. Clin. Invest. lower risk of cardiovascular disease. eases. Ann. Rheum. Dis. 60, 627–631. presses tumor necrosis factor-alpha 114, 805–812. Prostaglandins Leukot. Essent. Fatty Berg, K., Jynge, P., Bjerve, K., Skarra, biosynthesis via heme oxygenase-1 Funk, C. D. (2001). Prostaglandins and Acids 80, 51–56. S., Basu, S., and Wiseth, R. (2005). in human endothelial cells. Circ. Res. leukotrienes: advances in eicosanoid Helmersson, J., Larsson, A., Vessby, B., and Oxidative stress and inflammatory 104, 506–513. biology. Science 294, 1871–1875. Basu, S. (2005a). Active smoking and a

www.frontiersin.org October 2010 | Volume 1 | Article 116 | 5 Zhang et al. FP and cardiovascular disease

history of smoking are associated with Li, Y., Kang, J. X., and Leaf, A. (1997). PGF2alpha-associated vascular M., Hasumoto, K., Murata, T., Hirata, enhanced prostaglandin F(2alpha), Differential effects of various eicosa- smooth muscle hypertrophy is ROS M., Ushikubi, F., Negishi, M., Ichikawa, interleukin-6 and F2-isoprostane for- noids on the production or prevention dependent and involves the activa- A., and Narumiya, S. (1997). Failure mation in elderly men. Atherosclerosis of arrhythmias in cultured neonatal tion of mTOR, p70S6k, and PTEN. of parturition in mice lacking the 181, 201–207. rat cardiac myocytes. Prostaglandins Prostaglandins Other Lipid Mediat. . Science 277, Helmersson, J., Vessby, B., Larsson, A., 54, 511–530. 85, 49–57. 681–683. and Basu, S. (2005b). Cyclooxygenase- Morham, S. G., Langenbach, R., Loftin, Ross, R. (1999). Atherosclerosis – an Takayama, K., Yuhki, K., Ono, K., Fujino, mediated prostaglandin F2alpha C. D., Tiano, H. F., Vouloumanos, N., inflammatory disease. N. Engl. J. Med. T., Hara, A., Yamada, T., Kuriyama, S., is decreased in an elderly popula- Jennette, J. C., Mahler, J. F., Kluckman, 340, 115–126. Karibe, H., Okada, Y., Takahata, O., tion treated with low-dose aspirin. K. D., Ledford, A., Lee, C. A., and Saito, O., Guan, Y., Qi, Z., Davis, L. S., Taniguchi, T., Iijima, T., Iwasaki, H., Prostaglandins Leukot. Essent. Fatty Smithies, O. (1995). Prostaglandin Komhoff, M., Sugimoto, Y., Narumiya, Narumiya, S., and Ushikubi, F. (2005). Acids 72, 227–233. synthase 2 gene disruption causes S., Breyer, R. M., and Breyer, M. D. Thromboxane A2 and prostaglandin Helmersson, J., Vessby, B., Larsson, A., severe renal pathology in the mouse. (2003). Expression of the prostag- F2alpha mediate inflammatory tachy- and Basu, S. (2004). Association of Cell 83, 473–482. landin F receptor (FP) gene along cardia. Nat. Med. 11, 562–566. type 2 diabetes with cyclooxygenase- Mukhopadhyay, P., Bian, L., Yin, H., the mouse genitourinary tract. Tilley, S. L., Coffman, T. M., and Koller, B. ­mediated inflammation and oxida- Bhattacherjee, P., and Paterson, C. Am. J. Physiol. Renal Physiol. 284, H. (2001). Mixed messages: modula- tive stress in an elderly population. (2001). Localization of EP(1) and F1164–F1170. tion of inflammation and immune Circulation 109, 1729–1734. FP receptors in human ocular tis- Sales, K. J., Milne, S. A., Williams, A. R., responses by prostaglandins and Hirst, J. J., Parkington, H. C., Young, I. R., sues by in situ hybridization. Invest. Anderson, R. A., and Jabbour, H. N. thromboxanes. J. Clin. Invest. 108, Palliser, H. K., Peri, K. G., and Olson, Ophthalmol. Vis. Sci. 42, 424–428. (2004). Expression, localization, and 15–23. D. M. (2005). Delay of preterm birth Narumiya, S., and FitzGerald, G. A. signaling of prostaglandin F2 alpha Trang, L. E., Granstrom, E., and Lovgren, in sheep by THG113.31, a prostaglan- (2001). Genetic and pharmacological receptor in human endometrial adeno- O. (1977). Levels of prostaglandins F2 din F2alpha receptor antagonist. Am. J. analysis of prostanoid receptor func- carcinoma: regulation of proliferation alpha and E2 and thromboxane B2 in Obstet. Gynecol. 193, 256–266. tion. J. Clin. Invest. 108, 25–30. by activation of the epidermal growth joint fluid in rheumatoid arthritis. Ishida, N., Odani-Kawabata, N., Shimazaki, Narumiya, S., Sugimoto, Y., and Ushikubi, factor receptor and mitogen-activated Scand. J. Rheumatol. 6, 151–154. A., and Hara, H. (2006). Prostanoids in F. (1999). Prostanoid receptors: protein kinase signaling pathways. J. Wang, D., Patel, V. V., Ricciotti, E., Zhou, the therapy of glaucoma. Cardiovasc. structures, properties, and functions. Clin. Endocrinol. Metab. 89, 986–993. R., Levin, M. D., Gao, E., Yu, Z., Ferrari, Drug Rev. 24, 1–10. Physiol. Rev. 79, 1193–1226. Scher, J. U., and Pillinger, M. H. (2009). V. A., Lu, M. M., Xu, J., Zhang, H., Karmazyn, M., Tani, M., and Neely, J. R. Oga, T., Matsuoka, T., Yao, C., Nonomura, The anti-inflammatory effects of Hui, Y., Cheng, Y., Petrenko, N., Yu, (1993). Effect of prostaglandins I2 K., Kitaoka, S., Sakata, D., Kita, Y., prostaglandins. J. Investig. Med. 57, Y., and FitzGerald, G. A. (2009). (prostacyclin) and F2 alpha on func- Tanizawa, K., Taguchi, Y., Chin, 703–708. Cardiomyocyte cyclooxygenase-2 tion, energy metabolism, and calcium K., Mishima, M., Shimizu, T., and Seppala, E. (1987). Production of pros- influences cardiac rhythm and func- uptake in ischaemic/reperfused hearts. Narumiya, S. (2009). Prostaglandin tanoids by rheumatic synovial cells tion. Proc. Natl. Acad. Sci. U.S.A. 106, Cardiovasc. Res. 27, 396–402. F(2alpha) receptor signaling facili- in vitro: effects of anti-inflammatory 7548–7552. Kobayashi, T., Tahara, Y., Matsumoto, M., tates bleomycin-induced pulmonary drugs on arachidonic acid metabo- Watanabe, K., Yoshida, R., Shimizu, T., and Iguchi, M., Sano, H., Murayama, T., fibrosis independently of transform- lism. Clin. Rheumatol. 6, 170–176. Hayaishi, O. (1985). Enzymatic forma- Arai, H., Oida, H., Yurugi-Kobayashi, ing growth factor-beta. Nat. Med. 15, Sharif, N. A., Crider, J. Y., and Davis, T. tion of prostaglandin F2 alpha from T., Yamashita, J. K., Katagiri, H., 1426–1430. L. (2000). AL-3138 antagonizes FP prostaglandin H2 and D2. Purification Majima, M., Yokode, M., Kita, T., Olson, D. M. (2005). The promise of prostanoid receptor-mediated inositol and properties of prostaglandin F and Narumiya, S. (2004). Roles of prostaglandins: have they fulfilled phosphates generation: comparison synthetase from bovine lung. J. Biol. thromboxane A(2) and prostacyclin their potential as therapeutic targets with some purported FP antagonists. J. Chem. 260, 7035–7041. in the development of atherosclerosis for the delay of preterm birth? J. Soc. Pharm. Pharmacol. 52, 1529–1539. Watanabe, T., Nakao, A., Emerling, D., in apoE-deficient mice. J. Clin. Invest. Gynecol. Investig. 12, 466–478. Sinaiko, A. R., Steinberger, J., Moran, A., Hashimoto, Y., Tsukamoto, K., Horie, 114, 784–794. Peri, K. G., Quiniou, C., Hou, X., Abran, Prineas, R. J., Vessby, B., Basu, S., Tracy, Y., Kinoshita, M., and Kurokawa, Kunapuli, P., Lawson, J. A., Rokach, J., and D., Varma, D. R., Lubell, W. D., and R., and Jacobs, D. R. Jr. (2005). Relation K. (1994). Prostaglandin F2 alpha FitzGerald, G. A. (1997). Functional Chemtob, S. (2002). THG113: a novel of body mass index and insulin resist- enhances tyrosine phosphorylation characterization of the ocular pros- selective FP antagonist that delays ance to cardiovascular risk factors, and DNA synthesis through phos- taglandin f2alpha (PGF2alpha) recep- preterm labor. Semin. Perinatol. 26, inflammatory factors, and oxidative pholipase C-coupled receptor via tor. Activation by the isoprostane, 389–397. stress during adolescence. Circulation Ca(2+)-dependent intracellular path- 12-iso-PGF2alpha. J. Biol. Chem. 272, Pierce, K. L., Fujino, H., Srinivasan, D., 111, 1985–1991. way in NIH-3T3 cells. J. Biol. Chem. 27147–27154. and Regan, J. W. (1999). Activation of Smith, W. L., DeWitt, D. L., and Garavito, 269, 17619–17625. Lai, J., Jin, H., Yang, R., Winer, J., Li, W., FP prostanoid receptor isoforms leads R. M. (2000). Cyclooxygenases: struc- Weinreb, R. N., Toris, C. B., Gabelt, B. Yen, R., King, K. L., Zeigler, F., Ko, A., to Rho-mediated changes in cell mor- tural, cellular, and molecular biology. T., Lindsey, J. D., and Kaufman, P. L. Cheng, J., Bunting, S., and Paoni, N. F. phology and in the cell cytoskeleton. J. Annu. Rev. Biochem. 69, 145–182. (2002). Effects of prostaglandins on (1996). Prostaglandin F2 alpha induces Biol. Chem. 274, 35944–35949. Smyth, E. M., Grosser, T., Wang, M., the aqueous humor outflow path- cardiac myocyte hypertrophy in vitro Rabinowitz, B., Arad, M., Elazar, E., Klein, Yu, Y., and FitzGerald, G. A. (2009). ways. Surv. Ophthalmol. 47(Suppl. 1), and cardiac growth in vivo. Am. J. R., and Har Zahav, Y. (1992). Epicardial Prostanoids in health and disease. J. S53–S64. Physiol. 271(Pt 2), H2197–H2208. versus endocardial “in mirror” changes Lipid Res. 50(Suppl.), S423–S428. Whittle, B. J., Hansen, D., and Salmon, J. Langenbach, R., Morham, S. G., Tiano, in prostaglandin synthesis after short Sugimoto, Y., Hasumoto, K., Namba, A. (1985a). Gastric ulcer formation H. F., Loftin, C. D., Ghanayem, B. I., periods of ischemia and reperfusion. T., Irie, A., Katsuyama, M., Negishi, and cyclo-oxygenase inhibition in cat Chulada, P. C., Mahler, J. F., Lee, C. Eicosanoids 5, 163–167. M., Kakizuka, A., Narumiya, S., and antrum follows parenteral administra- A., Goulding, E. H., Kluckman, K. D., Rader, D. J., and Daugherty, A. (2008). Ichikawa, A. (1994). Cloning and tion of aspirin but not salicylate. Eur. Kim, H. S., and Smithies, O. (1995). Translating molecular discoveries expression of a cDNA for mouse J. Pharmacol. 116, 153–157. Prostaglandin synthase 1 gene dis- into new therapies for atherosclerosis. prostaglandin F receptor. J. Biol. Chem. Whittle, B. J., Oren-Wolman, N., and Guth, ruption in mice reduces arachidonic Nature 451, 904–913. 269, 1356–1360. P. H. (1985b). Gastric vasoconstrictor acid-induced inflammation and Rice, K. M., Uddemarri, S., Desai, D. H., Sugimoto, Y., Yamasaki, A., Segi, E., actions of leukotriene C4, PGF2 alpha, indomethacin-induced gastric ulcera- Morrison, R. G., Harris, R., Wright, Tsuboi, K., Aze, Y., Nishimura, T., Oida, and thromboxane mimetic U-46619 tion. Cell 83, 483–492. G. L., and Blough, E. R. (2008). H., Yoshida, N., Tanaka, T., Katsuyama, on rat submucosal microcirculation

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in vivo. Am. J. Physiol. 248(Pt 1), ­generated from the isoprostane (2006). Genetic model of selective could be construed as a potential conflict G580–G586. ­pathway and not the cyclooxygenase in COX2 inhibition reveals novel het- of interest. Wohlin, M., Helmersson, J., Sundstrom, humans. J. Biol. Chem. 282, 329–336. erodimer signaling. Nat. Med. 12, J., Arnlov, J., Vessby, B., Larsson, A., Yoshida, M., Sagawa, N., Itoh, H., Yura, S., 699–704. Received: 01 May 2010; paper pending pub- Andren, B., Lind, L., and Basu, S. Takemura, M., Wada, Y., Sato, T., Ito, Yu, Y., and Funk, C. D. (2007). A novel lished: 19 May 2010; accepted: 17 August (2007). Both cyclooxygenase- and A., and Fujii, S. (2002). Prostaglandin genetic model of selective COX-2 2010; published online: 14 October 2010. cytokine-mediated inflammation are F(2alpha), cytokines and cyclic inhibition: comparison with COX-2 Citation: Zhang J, Gong Y and Yu Y (2010)

associated with carotid intima-media mechanical stretch augment matrix null mice. Prostaglandins Other Lipid Prostaglandin F2α receptor: a promising thickness. Cytokine 38, 130–136. metalloproteinase-1 secretion from Mediat. 82, 77–84. therapeutic target for cardiovascular dis- Wong, S. L., Leung, F. P., Lau, C. W., Au, cultured human uterine cervical Yu, Y., Lucitt, M. B., Stubbe, J., Cheng, Y., ease. Front. Pharmacol. 1:116. doi: 10.3389/ C. L., Yung, L. M., Yao, X., Chen, Z. fibroblast cells. Mol. Hum. Reprod. 8, Friis, U. G., Hansen, P. B., Jensen, B. fphar.2010.00116 Y., Vanhoutte, P. M., Gollasch, M., and 681–687. L., Smyth, E. M., and FitzGerald, G. A. This article was submitted to Frontiers in Huang, Y. (2009). Cyclooxygenase- Yu, Y., Cheng, Y., Fan, J., Chen, X. S., Klein- (2009). Prostaglandin F2alpha elevates Inflammation Pharmacology, a specialty of 2-derived prostaglandin F2alpha Szanto, A., Fitzgerald, G. A., and Funk, blood pressure and promotes athero- Frontiers in Pharmacology. mediates endothelium-dependent C. D. (2005). Differential impact of sclerosis. Proc. Natl. Acad. Sci. U.S.A. Copyright © 2010 Zhang, Gong and Yu. This contractions in the aortae of hamsters prostaglandin H synthase 1 knock- 106, 7985–7990. is an open-access article subject to an exclusive with increased impact during aging. down on platelets and parturition. J. license agreement between the authors and Circ. Res. 104, 228–235. Clin. Invest. 115, 986–995. Conflict of Interest Statement: The the Frontiers Research Foundation, which Yin, H., Gao, L., Tai, H. H., Murphey, L. J., Yu, Y., Fan, J., Chen, X. S., Wang, D., authors declare that the research was permits unrestricted use, distribution, and Porter, N. A., and Morrow, J. D. (2007). Klein-Szanto, A. J., Campbell, R. L., conducted in the absence of any com- reproduction in any medium, provided the Urinary prostaglandin F2alpha is FitzGerald, G. A., and Funk, C. D. mercial or financial relationships that original authors and source are credited.

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