Hematopoietic prostaglandin D synthase (H-Pgds) is expressed in the early embryonic gonad and participates to the initial nuclear translocation of the SOX9 protein.

In mammals, the Prostaglandin D(2) (PGD(2) ) signaling pathway is involved in male gonadal development, regulating Sox9 gene expression and SOX9 protein subcellular localization through lipocalin prostaglandin D synthase (L-Pgds) activity. Nevertheless, because L-Pgds is downstream of Sox9, its expression cannot explain the initial nuclear translocation of the SOX9 protein. Here, we show that another source of PGD(2) , hematopoietic-Pgds (H-Pgds) enzyme is expressed in somatic and germ cells of the embryonic gonad of both sexes, as early as embryonic day (E) 10.5, before the onset of L-Pgds expression. Inhibition of H-Pgds activity by the specific HQL-79 inhibitor leads to impaired nuclear translocation of SOX9 protein in E11.5 Sertoli cells. Furthermore, analysis of H-Pgds(-/-) male embryonic gonads confirms abnormal subcellular localization of SOX9 protein at the E11.5 early stage of mouse testicular differentiation suggesting a role for H-Pgds-produced PGD(2) in the initial nuclear translocation of SOX9.

Knockout of the l-pgds gene aggravates obesity and atherosclerosis in mice.

This study was designed to determine whether lipocalin type-prostaglandin D synthase (l-pgds) deficiency contributes to atherogenesis using gene knockout (KO) mice. A high-fat diet was given to 8-week-old C57BL/6 (wild type; WT), l-pgds KO (LKO), apolipoprotein E (apo E) KO (AKO) and l-pgds/apo E double KO (DKO) mice. The l-pgds deficient mice showed significantly increased body weight, which was accompanied by increased size of subcutaneous and visceral fat tissues. Fat deposition in the aortic wall induced by the high-fat diet was significantly increased in LKO mice compared with WT mice, although there was no significant difference between AKO and DKO mice. In LKO mice, atherosclerotic plaque in the aortic root was also increased and, furthermore, macrophage cellularity and the expression of pro-inflammatory cytokines such as interleukin-1beta and monocyte chemoattractant protein-1 were significant increased. In conclusion, l-pgds deficiency induces obesity and facilitates atherosclerosis, probably through the regulation of inflammatory responses.

Complement C5a stimulates food intake via a prostaglandin D(2)- and neuropeptide Y-dependent mechanism in mice.

We have recently found that prostaglandin (PG) D(2) stimulates food intake via DP(1) receptor. Here we show that complement C5a stimulates food intake by activating the orexigenic PGD(2) system. C5a (30-100 pmol/mouse), after intracerebroventricular administration, stimulated food intake in non-food-deprived mice. The orexigenic activity of C5a was blocked by co-administration of a DP(1) receptor antagonist, BWA868C. Central administration of C5a elevated the hypothalamic mRNA expression of COX-2 but not COX-1, and the food intake stimulation of C5a was inhibited by pretreatment with a COX-2 inhibitor, celecoxib, suggesting that C5a activates COX-2 upstream of the PGD(2)-DP(1) system. The orexigenic activity of C5a was also inhibited by an antagonist for neuropeptide Y (NPY) Y(1) receptor, which was activated downstream of the PGD(2)-DP(1) system. These results suggest that C5a stimulates food intake via a PGD(2)- and NPY-dependent mechanism. C5a is the first example of orexigenic peptides acting through the PGD(2)-NPY system in the central nervous system.

Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine.

Caffeine, a component of tea, coffee and cola, induces wakefulness. It binds to adenosine A1 and A2A receptors as an antagonist, but the receptor subtype mediating caffeine-induced wakefulness remains unclear. Here we report that caffeine at 5, 10 and 15 mg kg(-1) increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2A receptor knockout mice. Thus, caffeine-induced wakefulness depends on adenosine A2A receptors.

Hematopoietic prostaglandin D synthase suppresses intestinal adenomas in ApcMin/+ mice.

Aspirin and other nonsteroidal anti-inflammatory drugs prevent some cases of colon cancer by inhibiting prostaglandin (PG) synthesis. PGE(2) promotes colon neoplasia, as shown by knockout mouse studies on enzymes and receptors in the PG cascade. A few experiments 20 to 30 years ago suggested that PGD(2) may suppress tumors, but a role for biosynthetic enzymes for PGD(2) in tumor development has not been studied. We report here that disruption of the gene for hematopoietic PGD synthase in Apc(Min/+) mice led to approximately 50% more intestinal adenomas compared with controls. Tumor size was not affected. By immunohistochemistry, we detected hematopoietic PGD synthase mainly in macrophages and monocytes of the gut mucosa. The mean number of tumors did not increase with knockout of the gene for the lipocalin type of the enzyme, which is not produced in the intestine. On the other hand, Apc(Min/+) mice with transgenic human hematopoietic PGD synthase tended to have 80% fewer intestinal adenomas. The transgene produced high mRNA levels (375-fold over endogenous). There was a suggestion of higher urinary excretion of 11beta-PGF(2alpha) and a lower excretion of a PGE(2) metabolite in transgenic mice, but differences (30-40%) were not statistically significant. The results support an interpretation that hematopoietic PGD synthase controls an inhibitory effect on intestinal tumors. Further studies will be needed to prove possible mechanisms, such as routing of PG production away from protumorigenic PGE(2) or inhibition of the nuclear factor-kappaB cascade by PGD(2) metabolites.

Central prostaglandin D(2) stimulates food intake via the neuropeptide Y system in mice.

We found that prostaglandin (PG) D(2), the most abundant PG in the central nervous system, stimulates food intake after intracerebroventricular administration in mice. The orexigenic effect of PGD(2) was mimicked by a selective agonist for the DP(1) receptor among two receptor subtypes for PGD(2), and abolished by its antagonist. Central administration of an antagonist or antisense oligodeoxynucleotide for the DP(1) receptor remarkably decreased food intake, body weight and fat mass. Hypothalamic mRNA levels of lipocalin-type PGD synthase were up-regulated after fasting. The orexigenic activity of PGD(2) was also abolished by an antagonist for neuropeptide Y (NPY) Y(1) receptor. Taken together, PGD(2) may stimulate food intake through central DP(1) receptor coupled to the NPY system.

Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects.

Recent studies suggest that lipocalin-type prostaglandin (PG) D synthase (L-PGDS), which converts PGH2 to PGD2, is implicated in the pathogenesis of atherosclerosis. However, clinical evidence for the association between serum L-PGDS levels and atherosclerosis has not been reported. In this study, we measured the serum L-PGDS concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and investigated the association with traditional cardiovascular risk factors and surrogate atherosclerotic indices, such as the maximum score of the intima-media complex thickness of the carotid artery (C-IMT(max)) and the brachial-ankle pulse wave velocity (ba-PWV), in 500 non-treated asymptomatic subjects. The serum concentration of L-PGDS was 0.56+/-0.01 (mean+/-SEM, range 0.25-1.27, median 0.54) mg/L. Serum L-PGDS levels increased with age and were higher in men than in women. Serum L-PGDS was higher in subjects with hypertension and increased with increasing numbers of the traditional atherosclerotic risk factors. When the subjects were divided into four groups according to the levels of serum L-PGDS, the age-adjusted values of C-IMT(max) and ba-PWV were significantly increased in subjects with higher serum L-PGDS levels (quartile 3 and quartile 4) compared to those in the lowest quartile (quartile 1), for both genders. Multiple regression analysis including risk factors revealed that serum L-PGDS was an independent determinant for ba-PWV (beta=0.130, p<0.001). Serum L-PGDS tended to associate with C-IMT(max) but was not statistically significant (beta=0.084, p=0.075). In conclusion, our results suggest that an increase in serum L-PGDS concentration is associated with the progression of atherosclerosis.

Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher.

Prostaglandin (PG) D2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD2 involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, including that which occurs during demyelination. Using the genetic demyelination mouse twitcher, a model of human Krabbe's disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP1 receptor for PGD2 in the brain of these mice. Cultured microglia actively produced PGD2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD2 receptor, DP1 and DP2, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD2 plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD2/DP signaling pathway using HPGDS- or DP1-null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine), resulted in remarkable suppression of astrogliosis and demyelination, as well as a reduction in twitching and spasticity. Furthermore, we found that the degree of oligodendroglial apoptosis was also reduced in HPGDS-null and HQL-79-treated twitcher mice. These results suggest that PGD2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.

Expression of prostaglandin D2 synthase in activated eosinophils in nasal polyps.

OBJECTIVE: To clarify the relationship between prostaglandin D2 production and eosinophil accumulation. DESIGN: Screening and diagnostic tests. SUBJECTS: Nineteen patients with chronic rhinosinusitis. INTERVENTIONS: Nasal polyps were obtained from 19 patients at endoscopic sinus surgery. Eosinophils in nasal polyps were counted after hematoxylin-eosin staining and immunostaining with antibodies against 2 eosinophil markers-major basic protein and EG2. Hematopoietic prostaglandin D2 synthase (HPGDS) expression was examined by semiquantitative Western blot analysis and by immunohistochemical staining with anti-HPGDS antibody. RESULTS: Nasal polyps were divided into 3 groups by the degree of eosinophilic infiltration. Western blot analysis revealed that HPGDS was more intensely and frequently expressed in the group with high infiltration than in the groups with low or medium infiltration. Hematopoietic prostaglandin D2 synthase was immunohistochemically found in a subpopulation of EG2-positive eosinophils that had accumulated in the nasal polyps but not in the EG2-negative resting eosinophils. The ratio of HPGDS-positive eosinophils to EG2-positive eosinophils in the group with high eosinophil infiltration (mean+/-SD, 64.8%+/-19.2%) was twice that in the group with low eosinophil infiltration (30.5%+/-13.8%). CONCLUSION: Prostaglandin D2 was actively produced by an EG2 and HPGDS double-positive subpopulation of activated eosinophils that had infiltrated into nasal polyps.

Fasting-induced reduction in locomotor activity and reduced response of orexin neurons in carnitine-deficient mice.

We found reduced locomotor activity (LA) under fasting in systemic carnitine-deficient juvenile visceral steatosis (jvs(-/-)) mice. When food was withdrawn at 8:00 a.m. (lights-off at 7:00 p.m., 12h/cycle), the nocturnal LA of jvs(-/-) mice was much less than the control (jvs(+/+) and jvs(+/-)) mice. LA recovered under carnitine or sucrose administration, but not under medium-chain triglyceride. In addition, fasted jvs(-/-) mice, without any energy supply, were activated by modafinil, a stimulator of the dopamine pathway. These results suggest that the reduced LA is not adequately explained by energy deficit. As the fasted jvs(-/-) mice showed lower body core temperature (BT), we examined the central nervous system regulating LA and BT. We found lower percentage of c-Fos positive orexin neurons in the lateral hypothalamus and reduced orexin-A concentration in the cerebrospinal fluid of fasted jvs(-/-) mice. Sleep analysis revealed that fasted jvs(-/-) mice had disruption of prolonged wakefulness, with a higher frequency of brief episodes of non-REM sleep during the dark period than fasted jvs(+/+) mice. These results strongly suggest that the reduced LA in fasted jvs(-/-) mice is related to the inhibition of orexin neuronal activity.

Perineuronal oligodendrocytes protect against neuronal apoptosis through the production of lipocalin-type prostaglandin D synthase in a genetic demyelinating model.

The genetic demyelinating mouse "twitcher" is a model of the human globoid cell leukodystrophy, caused by galactosylceramidase (GALC) deficiency. Demyelination in the twitcher brain is secondary to apoptotic death of oligodendrocytes (OLs). Lipocalin-type prostaglandin (PG) D synthase (L-PGDS), a protein expressed in mature OLs, was progressively upregulated in twitcher OLs; whereas expression of OL-associated proteins such as carbonic anhydrase II, myelin basic protein, and myelin-associated glycoprotein was downregulated during demyelination in twitcher brains. The upregulation of L-PGDS was more remarkable in perineuronal OLs than in interfascicular OLs. A larger number of L-PGDS-positive OLs was found in selected fiber tracts of twitcher brains where fewer apoptotic cells were detected. The distribution of L-PGDS-positive OLs was inversely related to the severity of demyelination, as assessed by accumulation of scavenger macrophages. Mice doubly deficient for L-PGDS and GALC disclosed a large number of apoptotic neurons, which were never seen in twitcher brains, in addition to an increased number of apoptotic OLs. A linear positive correlation was observed between the population of L-PGDS-positive OLs in the twitcher brain and the ratio of apoptotic nuclei in the double mutant versus those in the twitcher, suggesting a dose-dependent effect of L-PGDS against apoptosis. These lines of evidence suggest that L-PGDS is an anti-apoptotic molecule protecting neurons and OLs from apoptosis in the twitcher mouse. This is a novel example of OL-neuronal interaction.

Localization of various secretory phospholipase A2 enzymes in male reproductive organs.

Current evidence suggests the presence of transcripts for several secretory phospholipase A(2) (sPLA(2)) enzymes in male genital organs. In this study, we examined by immunohistochemistry the localization of group IIA, IIC, IID, IIE, IIF, V and X sPLA(2)s in male genital organs. In sPLA(2)-IIA-deficient C57BL/6 mouse testis, sPLA(2)-IIC, -IID, -IIE, -IIF, -V and -X were diversely expressed in spermatogenic cells within the seminiferous tubules. Immunoblotting revealed the presence of these sPLA(2)s in mouse spermatozoa. In addition, sPLA(2)-IIF, -V and -X were localized in the interstitial Leydig cells. The same set of sPLA(2)s was detected in a mouse cultured Leydig cell line, and adenovirus-mediated transfer of these sPLA(2)s into Leydig cells resulted in increased prostaglandin production. sPLA(2)-IIC, -IID, -IIE, -IIF, -V and -X were also detected diversely in the epithelium of the epididymis, vas deferens, seminal vesicles, and prostate. In a sPLA(2)-IIA-positive FVB strain, weak expression of sPLA(2)-IIA was detected in Leydig cells. Notable differences in the sPLA(2) expression profiles were found in the seminal vesicles and prostate between mice and humans. Taken together, individual sPLA(2)s exhibit distinct or partially overlapping localizations in male reproductive organs, suggesting both specific and redundant functions.

Arterial pressure and heart rate increase during REM sleep in adenosine A2A-receptor knockout mice, but not in wild-type mice.

Rapid eye movement (REM)-sleep related changes in arterial pressure (AP) and heart rate (HR) were observed in homozygous and heterozygous adenosine A(2A) receptor (A2AR) knockout (KO) mice, and the corresponding wild-type mice. During REM sleep, the mean AP (MAP) and HR were clearly increased in the homozygous A2AR KO mice, while, in the wild-type mice, they were decreased or maintained at the same level. Neither homozygous nor heterozygous A2AR KO mice showed significant difference in diurnal pattern and the hourly values of MAP and HR compared to the wild-type mice. From these findings, it is likely that the adenosine A2AR is involved in autonomic regulation during REM sleep.

Endogenous prostaglandin D(2) synthesis decreases vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells.

We examined the role of prostaglandin D(2) (PGD(2)) in the expression of vascular cell adhesion molecule-1 (VCAM)-1 following interleukin-1beta (IL-1) stimulation in human umbilical vein endothelial cells (HUVEC) transfected with lipocaline-type PGD(2) synthase (L-PGDS) genes. HUVEC were isolated from human umbilical vein and incubated with 20 U/ml IL-1 and various concentrations of authentic PGD(2). The isolated HUVEC were also transfected with L-PGDS genes by electroporation. The L-PGDS-transfected HUVEC were used to investigate the role of endogenous PGD(2) in IL-1-stimulated VCAM-1 biosynthesis. We also used an anti-PGD(2) antibody to examine whether an intracrine mechanism was involved in VCAM-1 production. PGD(2) and VCAM-1 levels were determined by radio- and cell surface enzyme-immunoassay, respectively. VCAM-1 mRNA was assessed by RT-PCR. IL-1-stimulated VCAM-1 expression by HUVEC was dose-dependently inhibited by authentic PGD(2). L-PGDS gene-transfected HUVEC produced more PGD(2) than HUVEC transfected with the reporter gene alone. IL-1 induced increases in VCAM-1 expression in HUVEC transfected with reporter genes alone. However, this effect was significantly attenuated in the case of IL-1 stimulation of HUVEC transfected with L-PGDS genes, and accompanied by an apparent suppression of VCAM-1 mRNA expression. Neutralization of extracellular PGD(2) by anti-PGD(2)-specific antibody influenced neither VCAM-1 mRNA expression nor VCAM-1 biosynthesis. In conclusion, HUVEC transfected with L-PGDS genes showed increased PGD(2) synthesis. This increase was associated with attenuation of both VCAM-1 expression and VCAM-1 mRNA expression. The results suggest that endogenous PGD(2) decreases VCAM-1 expression and VCAM-1 mRNA expression, probably through an intracrine mechanism.

Specific regulation of lipocalin-type prostaglandin D synthase in mouse heart by estrogen receptor beta.

Estrogens have important physiological roles in the cardiovascular system. We use DNA microarray technology to study the molecular mechanism of estrogen action in the heart and to identify novel estrogen-regulated genes. In this investigation we identify genes that are regulated by chronic estrogen treatment of mouse heart. We present our detailed characterization of one of these genes, lipocalin-type prostaglandin D synthase (L-PGDS). Northern and Western blot analysis revealed that L-PGDS was induced both by acute and chronic estrogen treatment. Northern blot analysis, using estrogen receptor (ER)-disrupted mice, suggests that L-PGDS is specifically induced by ERbeta in vivo. In further support of ERbeta-selective regulation, we identify a functional estrogen-responsive element in the L-PGDS promoter, the activity of which is up-regulated by ERbeta, but not by ERalpha. We demonstrate that a one-nucleotide change (A to C) in the L-PGDS estrogen-responsive element affects receptor selectivity.

Immunohistochemical localization of microsomal PGE synthase-1 and cyclooxygenases in male mouse reproductive organs.

We investigated the tissue distribution and cellular localization of microsomal PGE synthase-1 (mPGES-1) and cyclooxygenase (COX)-1 and -2 in the male mouse reproductive organs. Northern blotting revealed that the mPGES-1 mRNA was expressed intensely in the epididymis and weakly in the lung, spleen, skin, kidney, colon, and brain. In the male reproductive tract, the expression of mPGES-1 increased from the testis to the cauda epididymis and was highest in the vas deferens when examined by Northern blotting, RT-PCR, and Western blotting. By immunohistochemistry, mPGES-1 was detected in Leydig cells of the testis and in epithelial cells of the epididymis, vas deferens, and seminal vesicles. In addition, the caput and cauda regions of the epididymis and the vas deferens in this order showed a progressive increase in the expression of COX-1 mRNA and immunoreactivity, whereas COX-2 was dominantly expressed in the vas deferens. COX-1 was localized in epithelial cells of the caput, corpus and cauda epididymis and of the vas deferens, and COX-2 was evident in epithelial cells of the distal cauda epididymis and vas deferens. These results show that mPGES-1 is expressed coordinately with COX-1 and COX-2 and is involved in PGE(2) production in male genital organs.

Endogenous prostaglandin D2 synthesis reduces an increase in plasminogen activator inhibitor-1 following interleukin stimulation in bovine endothelial cells.

OBJECTIVE: We examined the role of prostaglandin D2 (PGD2) in the formation of plasminogen activator inhibitor (PAI)-1 following interleukin-1beta (IL-1) stimulation in bovine endothelial cells (EC) transfected with lipocaline-type PGD2 synthase (L-PGDS) genes. DESIGN AND METHODS: EC were isolated from bovine thoracic aorta and incubated with 20 U/ml IL-1 and various concentrations of authentic PGD2. The isolated EC were also transfected with L-PGDS genes by electroporation. The L-PGDS-transfected EC were used to investigate the role of endogenous PGD2 in IL-1 stimulated PAI-1 biosynthesis. We also used an anti-PGD2 antibody to examine whether an intracrine mechanism was involved in PAI-1 production. PGD2 and PAI-1 levels were determined by radio- and enzyme-immunoassay, respectively. PAI-1 mRNA was assessed by reverse transcription-polymerase chain reaction. RESULT: IL-1 stimulated PAI-1 production by EC was dose-dependently inhibited by authentic PGD2 at concentrations greater than 10-6 mol/l. L-PGDS gene-transfected EC produced more PGD2 than EC transfected with the reporter gene alone. IL-1 induced increases in PAI-1 production in EC transfected with reporter genes alone. However, this effect was significantly attenuated in the case of IL-1 stimulation of EC transfected with L-PGDS genes, and accompanied by an apparent suppression of PAI-1 mRNA expression. The effects of PGD2 on PAI-I formation were reversed to the basal levels by the inhibition of synthesis of endogenous PGD2. Neutralization of extracellular PGD2 by anti-PGD2 antibody influenced neither PAI-1 mRNA expression nor PAI-1 biosynthesis. CONCLUSION: EC transfected with L-PGDS genes increased PGD2 synthesis. This was associated with attenuation of both PAI-1 formation and PAI-1 mRNA expression. It is suggested that endogenous PGD2 decreases PAI-1 synthesis and PAI-1 mRNA expression, probably through an intracrine mechanism.

Extracellular histamine level in the frontal cortex is positively correlated with the amount of wakefulness in rats.

Histaminergic neurons have been strongly implicated in the regulation of wakefulness by activating cortical neurons. However, little is known about histamine release in the cortex during sleep-wake stages. In this study, we monitored the extracellular histamine level in the frontal cortex by in vivo microdialysis coupled with electroencephalogram and electromyogram recordings in freely moving rats. The histamine release was 3.8 times higher during wake episodes than during sleep episodes, being positively correlated (r = 0.845) with the time spent in wakefulness. These findings indicate that the histamine release in the cortex is strongly related to the sleep-wake cycle.

Lipocalin-type prostaglandin D synthase (beta-trace) in cerebrospinal fluid: a useful marker for the diagnosis of normal pressure hydrocephalus.

Lipocalin-type prostaglandin D synthase (PGDS) is considered to be mainly produced in the leptomeninges and secreted into cerebrospinal fluid (CSF). We found PGDS levels in CSF of patients with normal pressure hydrocephalus (NPH) (8.99+/-2.59 microg/ml, mean+/-S.D., n=14) to be significantly lower than levels in a control (15.29+/-5.17, n=14, P<0.0001) and other dementia group (19.14+/-4.34, n=7, P=0.0003). Thus, PGDS level in CSF is a useful marker for the differential diagnosis of NPH from other diseases with dementia.

Lipocalin-type and hematopoietic prostaglandin D synthases as a novel example of functional convergence.

Prostaglandin (PG) D2 is a major PG produced in the central nervous system and is involved in the regulation of sleep and pain responses through DP receptors. It is also actively produced by mast cells, basophils, and Th2 cells, acting as an allergic mediator through DP and CRTH2 receptors. PGD2 is further dehydrated to produce PGJ2, delta12-PGJ2, and 15-deoxy-delta(12,14)-PGJ2, the last being a ligand for the nuclear receptor PPARgamma. PGD synthase (PGDS) catalyzes the isomerization of PGH2 to PGD2 in the presence of sulfhydryl compounds. Two distinct types of PGDS have been identified: one is the lipocalin-type PGDS (L-PGDS); and the other, the hematopoietic PGDS (H-PGDS). We isolated the human and mouse cDNAs and genes for L-PGDS and H-PGDS, determined their X-ray crystallographic structures, examined their tissue distribution profiles and cellular localization, and generated gene-knockout mice and human enzyme-overexpressing transgenic mice. L-PGDS and H-PGDS are quite different from each other, in terms of their amino acid sequence, tertiary structure, evolutional origin, chromosomal and cellular localization, tissue distribution, and also functional relevance. Therefore, L-PGDS and H-PGDS are considered to be a novel example of functional convergence.