Yoshihiro Urade

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (411)1678.07 Total impact

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    ABSTRACT: Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of neuregulin 1 type III upregulated the prostaglandin D2 synthase (L-pgds, also known as Ptgds) gene, which, together with the G protein-coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.
    Nature neuroscience. 11/2014;
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    ABSTRACT: Through intercellular signalling, the somatic compartment of the foetal testis is able to program primordial germ cells to undergo spermatogenesis. Fibroblast growth factor 9 and several members of the transforming growth factor β superfamily are involved in this process in the foetal testis, counteracting the induction of meiosis by retinoic acid and activating germinal mitotic arrest. Here, using in vitro and in vivo approaches, we show that prostaglandin D2 (PGD2), which is produced through both L-Pgds and H-Pgds enzymatic activities in the somatic and germ cell compartments of the foetal testis, plays a role in mitotic arrest in male germ cells by activating the expression and nuclear localization of the CDK inhibitor p21(Cip1) and by repressing pluripotency markers. We show that PGD2 acts through its Dp2 receptor, at least in part through direct effects in germ cells, and contributes to the proper differentiation of male germ cells through the upregulation of the master gene Nanos2. Our data identify PGD2 signalling as an early pathway that acts in both paracrine and autocrine manners, and contributes to the differentiation of germ cells in the foetal testis.
    Development 08/2014; · 6.21 Impact Factor
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    ABSTRACT: Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the second major protein in human cerebrospinal fluid (CSF) and belongs to the lipocalin superfamily composed of various secretory lipophilic ligand transporter proteins. However, the endogenous ligand of L-PGDS has not yet been elucidated. In this study, we purified L-PGDS from the CSF of aneurysmal subarachnoid hemorrhage (SAH) patients. Lipocalin-type PG D synthase showed absorbance spectra with major peaks at 280 and 392 nm and a minor peak at around 660 nm. The absorbance at 392 nm of L-PGDS increased from 1 to 9 days and almost disappeared at 2 months after SAH, whereas the L-PGDS activity decreased from 1 to 7 days and recovered to normal at 2 months after SAH. These results indicate that some chromophore had accumulated in the CSF after SAH and bound to L-PGDS, thus inactivating it. Matrix assisted laser desorption ionization time-of-flight mass spectrometry of L-PGDS after digestion of it with endoproteinase Lys-C revealed that L-PGDS had covalently bound biliverdin, a by-product of heme breakdown. These results suggest that L-PGDS acted as a scavenger of biliverdin, which is a molecule not found in normal CSF. This is the first report of identification of a pathophysiologically important endogenous ligand for this lipocalin superfamily protein in humans.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 July 2014; doi:10.1038/jcbfm.2014.127.
    07/2014;
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    ABSTRACT: Compared with prostaglandin E2, which has an established role in cancer, the role of the COX metabolite prostaglandin D2 (PGD2) in chronic inflammation leading to tumorigenesis is uncertain. In this study, we investigated the role of PGD2 in colitis and colitis-associated colon cancer (CAC) using genetically modified mice and an established model of inflammatory colon carcinogenesis. Systemic genetic deficiency in hematopoietic PGD synthase (H-PGDS) aggravated colitis and accelerated tumor formation in a manner associated with increased TNFα expression. Treatment with a TNFα receptor antagonist attenuated colitis regardless of genotype. Histologic analysis revealed that infiltrated mast cells strongly expressed H-PGDS in inflamed colons. Mast cell-specific H-PGDS deficiency also aggravated colitis and accelerated CAC. In contrast, treatment with a PGD2 receptor agonist inhibited colitis and CAC. Together, our results identified mast cell-derived PGD2 as an inhibitor of colitis and CAC, with implications for its potential use in preventing or treating colon cancer. Cancer Res; 74(11); 3011-9. ©2014 AACR.
    Cancer research. 06/2014; 74(11):3011-3019.
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    ABSTRACT: Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Proton pump inhibitor (PPI) therapy improves subjective but not objective sleep parameters in patients with GERD. This study aimed to investigate the association between GERD and sleep, and the effect of PPI on sleep by using a rat model of chronic acid reflux esophagitis.
    PLoS ONE 05/2014; 9(9):e106969. · 3.53 Impact Factor
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    ABSTRACT: Idiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Abeta) implicated in Alzheimer's disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers. We evaluated 22 patients (age: 76.4 +/- 4.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Abeta42, Abeta40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score. L-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (p = 0.013 and p = 0.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman r = 0.753, p < 0.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman r = 0.602, p = 0.004), callosal angle (Spearman r = 0.592, p = 0.004), and ARWMC scores (Spearman r = 0.652, p = 0.001), but were negatively correlated with FAB scores (Spearman r = 0.641, p = 0.004). Our data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.
    Fluids and barriers of the CNS. 04/2014; 11(1):9.
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    ABSTRACT: An effective and safe treatment of insomnia in patients with neuropathic pain remains an unmet need. Melatonin and its analogs have been shown to have both analgesic and hypnotic effects; however, capacity of them on sleep disturbance with neuropathic pain as well as the precise mechanism is unclear. The present study evaluated effects of piromelatine, a novel melatonin receptor agonist, on sleep disturbance in a neuropathic pain-like condition as well as the underlying mechanisms. A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSL) was employed. The antinociceptive and hypnotic effects of piromelatine were evaluated by measurement of thermal hyperalgesia, mechanical allodynia, and electroencephalogram (EEG) recordings in PSL mice. Pharmacological approaches were used to clarify the mechanisms of action of piromelatine. PSL significantly lowered thermal and mechanical latencies and decreased non-rapid eye movement (NREM) sleep, and PSL mice exhibited sleep fragmentation. Treatment with 25, 50, or 100 mg/kg of piromelatine significantly prolonged thermal and mechanical latencies and increased NREM sleep. Moreover, the antinociceptive effect of piromelatine was prevented by melatonin antagonist luzindole, opioid receptor antagonist naloxone, or 5HT1A receptor antagonist WAY-100635. The hypnotic effect of piromelatine was blocked by luzindole but neither by naloxone nor WAY-100635. These data indicate that piromelatine is an effective treatment for both neuropathic pain and sleep disturbance in PSL mice. The antinociceptive effect of piromelatine is likely mediated by melatonin, opioid, and 5HT1A receptors; however, the hypnotic effect of piromelatine appears to be mediated by melatonin receptors.
    Psychopharmacology 04/2014; · 4.06 Impact Factor
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    ABSTRACT: Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in ApcMin/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced ApcMin/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced ApcMin/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in ApcMin/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. ApcMin/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors.
    Cancer Medicine 04/2014;
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    ABSTRACT: Our continuous survey of illegal products in Japan revealed the new distribution of 15 designer drugs. We identified four synthetic cannabinoids, i.e., NNEI (1), 5-fluoro-NNEI (2), 5-chloro-NNEI (3) and NNEI indazole analog (4), and seven cathinone derivatives, i.e., MPHP (5), α-PHPP (6), α-POP (7), 3,4-dimethoxy-α-PVP (8), 4-fluoro-α-PVP (9), α-ethylaminopentiophenone (10) and N-ethyl-4-methylpentedrone (11). We also determined LY-2183240 (12) and its 2'-isomer (13), which were reported to inhibit endocannabinoid uptake, a methylphenidate analog, 3,4-dichloromethylphenidate (14), and an MDA analog, 5-APDB (15). No chemical and pharmaceutical data for compounds 3, 4, 6 and 7 had been reported, making this the first report on these compounds.
    Forensic science international 03/2014; 243C:1-13. · 2.10 Impact Factor
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    ABSTRACT: Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5'-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a 'calm down' signal. DOI: http://dx.doi.org/10.7554/eLife.02172.001.
    eLife Sciences 03/2014; 3:e02172. · 8.52 Impact Factor
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    ABSTRACT: In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs. The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep-wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated. The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep-wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism. PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil. We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative-hypnotics.
    Psychopharmacology 02/2014; · 4.06 Impact Factor
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    ABSTRACT: The central opioid system is involved in a broadly distributed neural network that regulates food intake. Here we show that activation of central δ opioid receptor stimulated normal diet intake, but conversely suppressed high-fat diet intake. [D-Pen(2,5)]-enkephalin (DPDPE), an agonist selective for the δ receptor, increased normal diet intake after central administration to non-fasted male mice. The orexigenic activity of DPDPE was inhibited by blockade of cyclooxygenase (COX)-2, lipocalin-type prostaglandin D synthase (L-PGDS), DP1 and Y1 receptors for PGD2 and neuropeptide Y (NPY), respectively, suggesting that this was mediated by the PGD2-NPY system. In contrast, DPDPE decreased high-fat diet intake in mice fed a high-fat diet. DPDPE-induced high-fat diet intake suppression was blocked by antagonists of melanocortin 4 (MC4) and corticotropin-releasing factor (CRF) receptors, but not by genetical knockout of L-PGDS. These results suggest that central δ opioid receptor activation suppresses high-fat diet intake via the MC-CRF system, independently of the orexigenic PGD2 system. Furthermore, orally administered rubiscolin-6, an opioid peptide found in spinach Rubisco, suppressed high-fat diet intake, and this suppression was also blocked by centrally administered naltrindole, an antagonist for the δ receptor, suggesting that rubiscolin-6 suppressed high-fat diet intake via activation of central δ opioid receptor.
    AJP Regulatory Integrative and Comparative Physiology 01/2014; · 3.28 Impact Factor
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    ABSTRACT: The accurate and robust measurement of prostaglandins (PG) concentration could help to understand the many physiological functions. The present study revealed that liquid chromatography tandem mass spectrometry method for the PGs analysis can satisfy the requirements for both qualitative and quantitative performance as compared to competitive enzyme immunoassays.
    Journal of Bioscience and Bioengineering 01/2014; · 1.74 Impact Factor
  • Ko Fujimori, Yoshihiro Urade
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    ABSTRACT: Adipogenesis is controlled by complex mechanisms, and transcription factors are involved in its regulation. PPARγ is a ligand-dependent transcription factor and the most important one for adipogenesis. Although prostaglandin (PG) D2 metabolites have been reported as being the ligands of PPARγ, the endogenous PPARγ ligand in adipocytes remains unclear. Here, we show the methods for the general analysis of adipocyte differentiation and the protocols for promoter analysis, fluorescence EMSA, and chromatin immunoprecipitation assay for the transcriptional regulation of the SREBP-1c-activated lipocalin-type PGD synthase gene in adipocytes. Moreover, we describe that PGD2 and its metabolites are involved in the regulation of adipogenesis through PPARγ-dependent and -independent mechanisms.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1164:177-96. · 1.29 Impact Factor
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    ABSTRACT: Epilepsy is a neurological disorder with the occurrence of seizures, which are often accompanied by sleep. Prostaglandin (PG) D2 is produced by hematopoietic or lipocalin-type PGD synthase (H- or L-PGDS) and involved in the regulation of physiological sleep. Here, we show that H-PGDS, L/H-PGDS or DP1 receptor (DP1R) KO mice exhibited more intense pentylenetetrazole (PTZ)-induced seizures in terms of latency of seizure onset, duration of generalized tonic-clonic seizures, and number of seizure spikes. Seizures significantly increased the PGD2 content of the brain in wild-type mice. This PTZ-induced increase in PGD2 was attenuated in the brains of L- or H-PGDS KO and abolished in L/H-PGDS KO mice. Postictal non-rapid eye movement sleep was observed in the wild-type and H-PGDS or DP2R KO, but not in the L-, L/H-PGDS or DP1R KO, mice. These findings demonstrate that PGD2 produced by H-PGDS and acting on DP1R is essential for seizure suppression and that the L-PGDS/PGD2/DP1R system regulates sleep that follows seizures.
    Experimental Neurology 12/2013; · 4.65 Impact Factor
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    ABSTRACT: In humans, a first night effect (FNE) is characterized by increased sleep latency and decreased total sleep time in an unfamiliar environment, but the mechanism and treatment options for this universally experienced acute insomnia are unclear. We continuously recorded electroencephalography (EEG) and electromyogram (EMG) and measured plasma corticosterone levels to develop a mouse FNE model by inducing acute insomnia in mice that have been placed in unfamiliar cage environments. The sleep latency of mice 'moved to clean cages' (MCC) was longer than that for mice 'moved to dirty ones' (MDC). As compared to MDC mice, MCC mice showed stronger decreases in the amount of non-rapid eye movement (non-REM, NREM) and REM sleep, with a lower power density of NREM sleep, increased fragmentation and decreased stage transitions from NREM sleep to wake, and higher variation in plasma corticosterone levels. Treatment of MCC mice with zolpidem, diazepam, raclopride, pyrilamine, except SCH23390 shortened NREM sleep latency. In addition, zolpidem significantly increased NREM and REM sleep with the increase in slow wave activity (1.00-2.75Hz), while raclopride significantly increased NREM and REM sleep without changing the EEG power density in MCC mice, whereas diazepam increased sleep with a drastic decrease in power density of the frequency band between 1.00 and 4.00Hz, diazepam also increased the frequency band between 9.75 and 24.75Hz during NREM sleep. These results indicate that a MCC mouse can mimic a FNE phenotype of humans and that zolpidem and raclopride may be useful drugs to prevent acute insomnia, including FNE.
    Pharmacology Biochemistry and Behavior 12/2013; · 2.82 Impact Factor
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    ABSTRACT: The effects of PGD2 are extremely context dependent. It can have pro- or anti-inflammatory effects in clinically important pathological conditions. A greater mechanistic insight into the determinants of PGD2 activity during inflammation is thus required. In this study, we investigated the role of PGD2 in croton oil-induced dermatitis using transgenic (TG) mice overexpressing hematopoietic PGD synthase. Administration of croton oil caused tissue swelling and vascular leakage in the mouse ear. Compared with wild-type animals, TG mice produced more PGD2 and showed decreased inflammation in the early phase, but more severe manifestations during the late phase. Data obtained from bone marrow transplantation between wild-type and TG mice indicated that PGD2 produced by tissue resident cells in the TG mice attenuated early-phase inflammation, whereas PGD2 produced from hematopoietic lineage cells exacerbated late-phase inflammation. There are two distinct PGD2 receptors: D-prostanoid receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). In TG mice, treatment with a DP antagonist exacerbated inflammation in the early phase, whereas treatment with a CRTH2 antagonist attenuated inflammation during the late phase. In vitro experiments showed that DP agonism enhanced vascular endothelial barrier formation, whereas CRTH2 agonism stimulated neutrophil migration. Collectively, these results show that when hematopoietic PGD synthase is overexpressed, tissue resident cell-derived PGD2 suppresses skin inflammation via DP in the early phase, but hematopoietic lineage cell-derived PGD2 stimulates CRTH2 and promotes inflammation during the late phase. DP-mediated vascular barrier enhancement or CRTH2-mediated neutrophil activation may be responsible for these effects. Thus, PGD2 represents opposite roles in inflammation, depending on the disease phase in vivo.
    The Journal of Immunology 12/2013; · 5.52 Impact Factor
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    ABSTRACT: Prostaglandin E synthase (PGES) catalyzes the isomerization of PGH2 to PGE2. We previously reported the identification and structural characterization of Bombyx mori PGES (bmPGES), which belongs to Sigma-class glutathione transferase. Here, we extend these studies by determining the structure of bmPGES in complex with glutathione sulfonic acid (GTS) at a resolution of 1.37 Å using X-ray crystallography. GTS localized to the glutathione-binding site. We found that electron-sharing network of bmPGES includes Asn95, Asp96, and Arg98. Site-directed mutagenesis of these residues to create mutant forms of bmPGES mutants indicate that they contribute to catalytic activity. These results are, to our knowledge, the first to reveal the presence of an electron-sharing network in bmPGES.
    Biochemical and Biophysical Research Communications 10/2013; · 2.28 Impact Factor
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    ABSTRACT: We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia-reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)-derived PGD2 biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD2 biosynthesis. Acute PGD2 treatment did not protect hearts against I/R injury. We then speculated that PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2-like 2 (Nrf2) target genes in the heart in an L-PGDS-dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD2 receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF2α receptor (FP), which binds PGF2α and PGD2 with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts. PGD2 acted through its metabolite 15-deoxy-Δ12,14-PGJ2 in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS-dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD2 protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD2 (15-deoxy-Δ12,14-PGJ2) as another mechanism by which glucocorticoids induce cardioprotection.
    Hypertension 10/2013; · 6.87 Impact Factor
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Publication Stats

9k Citations
1,678.07 Total Impact Points

Institutions

  • 2013–2014
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
  • 1988–2014
    • Osaka Bioscience Institute
      Ōsaka, Ōsaka, Japan
  • 2010–2013
    • State Key Laboratory of Medical Genetics of China
      Ch’ang-sha-shih, Hunan, China
  • 2007–2013
    • Fudan University
      • • Department of Pharmacology
      • • State Key Laboratory of Medical Neurobiology
      Shanghai, Shanghai Shi, China
  • 2009–2012
    • Kansai Medical University
      • Department of Medical Chemistry
      Moriguchi, Osaka-fu, Japan
    • Osaka Prefecture University
      • Graduate School of Life and Environmental Sciences
      Sakai, Osaka-fu, Japan
    • University of Toyama
      • Graduate School of Innovative Life Science
      Тояма, Toyama, Japan
    • Molecular Biology Institute of Barcelona
      Barcino, Catalonia, Spain
  • 2008–2012
    • Osaka University of Pharmaceutical Sciences
      • Laboratory of Biodefense and Regulation
      Takatuki, Ōsaka, Japan
    • Japan Synchrotron Radiation Research Institute (JASRI)
      Tatsuno, Hyōgo, Japan
    • Saga University
      • Division of Cardiovascular & Renal Medicine
      Сага Япония, Saga, Japan
  • 1991–2012
    • Osaka University
      • • Division of Applied Chemistry
      • • Graduate School of Engineering
      • • Division of Obstetrics and Gynecology
      • • Research Institute for Microbial Diseases
      Suika, Ōsaka, Japan
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
  • 1982–2012
    • Kyoto University
      • • Division of Food Science and Biotechnology
      • • Graduate School of Pharmaceutical Sciences / Faculty of Pharmaceutical Sciences
      • • Graduate School of Medicine / Faculty of Medicine
      • • Department of Morphological Brain Science
      • • Department of Dermatology
      • • Department of Medical Chemistry
      Kyoto, Kyoto-fu, Japan
  • 2011
    • National Institute of Health Sciences, Japan
      Edo, Tōkyō, Japan
  • 1997–2011
    • Shiga University of Medical Science
      • Department of Cardiovascular and Respiratory Medicine
      Ōtu, Shiga, Japan
    • Kyushu Institute of Technology
      Hukuoka, Fukuoka, Japan
    • Kanazawa Medical University
      • Department of Neurosurgery
      Kanazawa-shi, Ishikawa-ken, Japan
    • Mount Sinai Hospital, Toronto
      • Department of Pathology and Laboratory Medicine
      Toronto, Ontario, Canada
  • 1993–2008
    • The University of Tokyo
      • • Faculty and Graduate School of Agriculture and Life Sceince
      • • School of Medicine
      • • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan
  • 2002–2007
    • Osaka City University
      • Department of Pediatrics
      Ōsaka, Ōsaka, Japan
  • 1985–2007
    • Osaka Medical College
      • Department of Otolaryngology
      Takatuki, Ōsaka, Japan
  • 2006
    • Yokohama City University
      • Department of Medicine
      Yokohama, Kanagawa, Japan
  • 2005
    • Winthrop University Hospital
      Mineola, New York, United States
    • University of Science and Technology of China
      • School of Life Sciences
      Hefei, Anhui Sheng, China
  • 1999–2004
    • Nagoya City University
      • Department of Neurosurgery (Hospital)
      Nagoya, Aichi, Japan
  • 2003
    • Waseda University
      • School of Human Sciences
      Tokyo, Tokyo-to, Japan
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2001
    • Dokkyo Medical University
      • Division of Cardiology and Pneumology
      Tochigi, Tochigi-ken, Japan
  • 1998–2001
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, MA, United States
  • 2000
    • Institute for Biomedical Research “Alberto Sols“
      Madrid, Madrid, Spain
  • 1998–2000
    • Pennsylvania State University
      • Department of Animal Science
      University Park, MD, United States
  • 1997–2000
    • The University of Tokushima
      • Department of Biochemistry
      Tokusima, Tokushima, Japan
  • 1997–1998
    • Spanish National Research Council
      Madrid, Madrid, Spain
  • 1989
    • Kyoto Prefectural University of Medicine
      Kioto, Kyōto, Japan