記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FASEB  

Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Although the prostaglandin (PG)I2 receptor IP is expressed broadly in the liver, the role of PGI2-IP signaling in the development of NASH remains to be determined. Here, we investigated the role of the PGI2-IP system in the development of steatohepatitis using micelacking the PGI2 receptor IP [IP-knockout (IP-KO) mice] and beraprost (BPS), a specific IP agonist. IP-KO and wild-type (WT) mice were fed a methionine- and choline-deficient diet (MCDD) for 2, 5, or 10 wk. BPS was administered orally to mice every day during the experimental periods. The effect of BPS on the expression of chemokine and inflammatory cytokines was examined also in cultured Kupffer cells. WT mice fed MCDD developedsteatohepatitis at 10 wk.IP-KO mice developed steatohepatitis at 5 wk with augmented histologic derangements accompanied by increased hepatic monocyte chemoattractant protein-1 (MCP-1) and TNF-α concentrations. After 10 wk of MCDD, IP-KO micehad greater hepatic irondeposition with prominent oxidative stress, resulting in hepatocyte damage. In WT mice, BPS improved histologic and biochemical parameters of steatohe-patitis, accompanied by reduced hepatic concentration of MCP-1 and TNF-α. Accordingly, BPS suppressed the LPS-stimulated Mcp-1 and Tnf-am RNA expression in cultured Kupffer cells prepared from WT mice. PGI2-IP signaling plays a crucial role in the development and progression of steatohepatitis by modulating the inflammatory response, leading to augmented oxidative stress. We suggest that the PGI2-IP system is an attractive therapeutic target for treating patients with NASH.

DOI： 10.1096/fj.201700590R

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Diethylstilbestrol (DES), a strong estrogenic compound, is well-known to affect the reproductive system. In this study, we investigated the effects of DES administration on gonadotropin levels and ovarian steroidogenesis in prepubertal rats. DES treatment acutely reduced serum LH levels, followed by a reduction in the expression of various steroidogenesis-related genes in theca cells. Serum FSH levels were almost unaffected by DES-treatment, even though Cyp19a1 expression was markedly reduced. Serum progesterone, testosterone and estradiol levels were also declined at this time. LH levels recovered from 12 h after DES-treatment and gradually increased until 96 h with a reduction of ER alpha expression observed in the pituitary. Steroidogenesis-related genes were also up-regulated during this time, except for Cyp17a1 and Cyp19a1. Consistent with observed gene expression pattern, serum testosterone and estradiol concentrations were maintained at lower levels, even though progesterone levels recovered. DES-treatment induced the inducible nitric oxide synthase (iNOS) in granulosa cells, and a nitric oxide generator markedly repressed Cyp19a1 expression in cultured granulosa cells. These results indicate that DES inhibits thecal androgen production via suppression of pituitary LH secretion and ovarian Cyp17a1 expression. In addition, DES represses Cyp19a1 expression by inducing iNOS gene expression for continuous inhibition of estrogen production in granulosa cells.

DOI： 10.1038/s41598-017-08780-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0037-1607979

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2340/00015555-2437

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ENDOCRINE SOC  

Context: 11-ketotestosterone (11-KT) is a novel class of active androgen. However, the detail of its synthesis remains unknown for humans.
Objective: The objective of this study was to clarify the production and properties of 11-KT in human.
Design, Participants, and Methods: Expression of cytochrome P450 and 11 beta-hydroxysteroid dehydrogenase types 1 and 2 (key enzymes involved in the synthesis of 11-KT) were investigated in human gonads. The production of 11-KT was investigated in Leydig cells. Plasma concentrations of testosterone and 11-KT were measured in 10 women and 10 men of reproductive age. Investigation of its properties was performed using breast cancer-derived MCF-7 cells.
Results: Cytochrome P450 and 11 beta-hydroxysteroid dehydrogenase types 1 and 2 were detected in Leydig cells and theca cells. Leydig cells produced 11-KT, and relatively high levels of plasma 11-KT were measured in both men and women. There was no sexual dimorphism in the plasma levels of 11-KT, even though testosterone levels were more than 20 times higher in men than in women. It is noteworthy that the levels of testosterone and 11-KT were similar in women. In a luciferase reporter system, 11-KT activated human androgen receptor-mediated transactivation. Conversely, 11-KT did not activate estrogen receptor-mediated transactivation in aromatase-expressed MCF-7 cells, whereas testosterone did following conversion to estrogen. 11-KT did not affect the estrogen/estrogen receptor -mediated cell proliferation of MCF-7 cells. Furthermore, it significantly inhibited cell proliferation when androgen receptor was transfected into MCF-7 cells.
Conclusions: The current study indicates that 11-KT is produced in the gonads and represents a major androgen in human. It can potentially serve as a nonaromatizable androgen.

DOI： 10.1210/jc.2016-2311

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

ONO-1301 [(E)-[5-[2-[1-phenyl-1-(3-pyridyl)methylidene-aminooxy] ethyl]-7,8-dihydronaphthalene-1-yloxy]acetic acid] is a novel prostaglandin (PG) I-2 mimetic with inhibitory activity on the thromboxane (TX) A(2) synthase. Interestingly, ONO-1301 retains its inhibitory effect on platelet aggregation after repeated administration, while beraprost, a representative agonist for the PGI(2) receptor (IP), loses its inhibitory effect after repeated administration. In the present study, we intended to clarify the mechanism by which ONO-1301 escapes desensitization of an antiplatelet effect. In platelets prepared from wild-type mice, ONO-1301 inhibited collagen-induced aggregation and stimulated cAMP production in an IP-dependent manner. In addition, ONO-1301 inhibited arachidonic acid-induced TXA(2) production in platelets lacking IP. Despite the decrease in stimulatory action on cAMP production, the antiplatelet effect of ONO-1301 hardly changed after repeated administration for 10 days in wild-type mice. Noteworthy, beraprost could retain its antiplatelet effect after repeated administration in combination with a low dose of ozagrel, a TXA(2) synthase inhibitor. Therefore, we hypothesized that chronic IP stimulation by beraprost induces an increase in TXA(2) production, leading to reduction in the antiplatelet effect. As expected, repeated administration of beraprost increased the plasma and urinary levels of a TXA(2) metabolite, while ONO-1301 did not increase them significantly. In addition, beraprost could retain the ability to inhibit platelet aggregation after repeated administration in mice lacking the TXA(2) receptor (TP). These results indicate that TP-mediated signaling participates in platelet desensitization against IP agonists and that simultaneous inhibition of TXA(2) production confers resistance against desensitization on IP agonists.

DOI： 10.1124/jpet.115.222612

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-12-0897

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Aromatase-deficient (ArKO) mice are totally anovulatory due to insufficient estrogen production. However, sequential administrations of high doses of 17 beta-estradiol (E2) and gonadotropins were found to induce ovulation in these mice. Here, we examined how the ovulatory stimulation for ArKO mice alters the expressions of genes related to prostaglandin (PG) E-2 metabolism and ovarian contents of PGE(2), as PGE(2) is one of the critical mediators of ovulatory induction. The ovulatory stimulation significantly increased mRNA expressions of prostaglandin-endoperoxide synthase 2, PGE(2) receptor type 4 and sulfotransferase family 1E, member 1, in preovulatory ArKO ovaries. In contrast, it suppressed the mRNA expression of 15-hydroxyprostaglandin dehydrogenase. Furthermore, significant elevation in the PGE2 contents was detected in the preovulatory ovaries of Ark mice after stimulation with E2 plus ovulatory doses of gonadotropins. Thus, these analyses demonstrate a requirement of E2 for the preovulatory enhancement of PGE(2) synthesis, leading to future success in ovulation. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2012.06.006

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DOI： 10.1038/ki.2012.115

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.pharmthera.2010.09.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN  

The effect of selective activation of platelet prostaglandin (PG) E-2 receptor subtype EP2 or EP4 on platelet aggregation remains to be determined. In platelets prepared from wild-type mice (WT platelets), high concentrations of PGE(2) inhibited platelet aggregation induced by U-46619, a thromboxane receptor agonist. However, there was no significant change in the inhibitory effect of PGE(2) on platelets lacking EP2 (EP2-/- platelets) and EP4 (EP4-/- platelets) compared with the inhibitory effect on WT platelets. On the other hand, AE1-259 and AE1-329, agonists for EP2 and EP4, respectively, potently inhibited U-46619-induced aggregation with respective IC50 values of 590 +/- 14 and 100 +/- 4.9 nM in WT platelets, while the inhibition was significantly blunted in EP2-/- and EP4-/- platelets. In human platelets, AE1-259 and AE1-329 inhibited U-46619-induced aggregation with respective IC50 values of 640 +/- 16 and 2.3 +/- 0.3 nM. Notably, the inhibitory potency of AE1-329 in human platelets was much higher than that in murine platelets, while such a difference was not observed in the inhibitory potency of AE1-259. AE1-329 also inhibited adenosine diphosphate-induced platelet aggregation, and the inhibition was almost completely blocked by AE3-208, an EP4 antagonist. In addition, AE1-329 increased intracellular cAMP concentrations in a concentration- and EP4-dependent manner in human platelets. These results indicate that selective activation of EP2 or EP4 can inhibit platelet aggregation and that EP4 agonists are particularly promising as novel anti-platelet agents.

DOI： 10.1160/TH10-01-0043

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/ATVBAHA.109.193730

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

Zymosan, the cell wall of Saccharomyces cerevisiae, induces innate immune responses involving prostanoid production and complement activation. However, the roles of prostanoids in zymosan-induced inflammation and their interaction with the complement system remain to be determined. To clarify these issues, we examined zymosan-induced pleurisy in mice lacking receptors for prostaglandin (PG) E 2 (EP-/- mice) or PGI(2) (IP-/- mice). Zymosan-induced exudate formation was significantly reduced in IP-/- mice compared with wild-type (WT) mice, whereas none of the EP-/- mice (EP1-/-, EP2-/-, EP3-/-, and EP4-/- mice) showed any significant difference from WT mice. Furthermore, indomethacin, an inhibitor of prostanoid biosynthesis, suppressed exudate formation in WT mice to almost the same level as that of IP-/- mice. Accordingly, significant production of PGI(2) in the pleural cavity, suggested to be cyclooxygenase-2-dependent, was observed after zymosan injection. Complement activation in the pleural cavity after zymosan injection was confirmed, and preinjection of cobra venom factor (CVF), to deplete blood complement C3, was significantly suppressed after zymosan-induced exudate formation in WT mice. Simultaneous treatment with indomethacin and CVF further suppressed exudate formation in WT mice compared with each treatment alone. Because, some degree of exudate formation was still observed, other factor(s) seem to be involved. However, platelet-activating factor, a promising candidate as one such factor, was not involved in zymosan-induced exudate formation. These results clearly indicate that the PGI(2)-IP system together with the complement system plays a key role in exudate formation in zymosan-induced pleurisy.

DOI： 10.1124/jpet.107.134494

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DOI： 10.1254/jphs.FP0050980

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

PGとTXよりなるプロスタノイドは,生体内でさまざまな作用を発揮する生理活性脂質である.また,その作用はおのおののプロスタノイドに特異的なレセプターを介して発揮される.一方,循環器系の臓器や細胞には,多種類のプロスタノイドレセプターが広く発現している.さらに,循環器系で認められるさまざまな病態に伴い,プロスタノイド産生が亢進することが知られており,その循環器系での作用が注目されてきた.しかし,これらプロスタノイドの作用が生理的・病態生理的にどの程度重要な役割を果たすのかに関し,いまだ不明な点が多い(著者抄録)

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/nm1005-1048

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background - In the heart, the expressions of several types of prostanoid receptors have been reported. However, their roles in cardiac hypertrophy in vivo remain unknown. We intended to clarify the roles of these receptors in pressure overload - induced cardiac hypertrophy using mice lacking each of their receptors.
Methods and Results - We used a model of pressure overload - induced cardiac hypertrophy produced by banding of the transverse aorta in female mice. In wild-type mice subjected to the banding, cardiac hypertrophy developed during the observation period of 8 weeks. In mice lacking the prostaglandin (PG) I-2 receptor (IP-/-), however, cardiac hypertrophy and cardiomyocyte hypertrophy were significantly greater than in wild-type mice at 2 and 4 weeks but not at 8 weeks, whereas there was no such augmentation in mice lacking the prostanoid receptors other than IP. In addition, cardiac fibrosis observed in wild-type hearts was augmented in IP (-/-) hearts, which persisted for up to 8 weeks. In IP (-/-) hearts, the expression level of mRNA for atrial natriuretic peptide, a representative marker of cardiac hypertrophy, was significantly higher than in wild-type hearts. In vitro, cicaprost, an IP agonist, reduced platelet-derived growth factor-induced proliferation of wild-type noncardiomyocytes, although it could not inhibit cardiotrophin-1-induced hypertrophy of cardiomyocytes. Accordingly, cicaprost increased cAMP concentration efficiently in noncardiomyocytes.
Conclusions - IP plays a suppressive role in the development of pressure overload - induced cardiac hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac fibrosis. Both effects have been suggested as originating from the action on noncardiomyocytes rather than cardiomyocytes.

DOI： 10.1161/CIRCULATIONAHA.104.527077

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system(1), definitive proof has been lacking. Prostanoids, including prostaglandin (PG) D-2, PGE(2), PGF(2α), PGI(2) and thromboxane (TX) A(2), exert their actions through specific receptors: DP, EP (EP1, EP2, EP3, EP4), FP, IP and TP, respectively(2). Here we have examined the roles of prostanoids in inflammatory tachycardia using mice that lack each of these receptors individually. The TXA(2) analog I-BOP and PGF(2α) each increased the beating rate of the isolated atrium of wild-type mice in vitro through interaction with TP and FP receptors, respectively. The cytokine- induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP receptors. The tachycardia induced in wild-type mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-deficient or FP-deficient mice and was completely absent in mice lacking both TP and FP. The β-blocker propranolol did not block the LPS-induced increase in heart rate in wildtype animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA(2) and PGF(2α) formed under systemic inflammatory conditions.

DOI： 10.1038/nm1231

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記述言語：日本語   出版者・発行元：(株)先端医学社  

プロスタノイドは,プロスタグランジン(PG)とトロンボキサン(TX)よりなる,一群の生理活性物質である.一方,レニンは腎血管性高血圧症の病態形成および塩類欠乏状態における体液保持機構として中心的な役割を果たしている.また,外来性に投与されたプロスタノイドのレニン分泌促進作用の報告はあるが,腎血管性高血圧症および塩類欠乏状態でのレニン分泌調節におけるプロスタノイドの役割は不明である.そこで,本研究は,各プロスタノイド受容体を欠損するマウスを用い,プロスタノイドのレニン分泌を介した腎血管性高血圧症の病態形成における役割の解明を目指した.その結果,PGI2は,腎血管性高血圧症および塩類欠乏状態の病態形成に重要な役割を果たすことが明らかとなった.また,その作用機構として,PGI2がレニンmRNAの発現を上昇させ,レニン分泌を促進することが解明された(著者抄録)

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

The roles of prostaglandins (PGs) as mediators of inflammation have been extensively studied, and production of PGI(2) and PGE(2) at inflammatory sites has been reported. However, it has not yet been clarified which type of PG receptors has a major role in inflammatory exudation. To examine in vivo role of PG receptors in inflammatory exudation, we induced pleurisy in PG receptors (IP, EP1, EP2, EP3, or EP4) knockout mice by intrapleural injection of carrageenin. Pleural exudate accumulation in wild-type (WT) mice at 1 to 5 h, but not at 24 h, was significantly attenuated by the pretreatment with indomethacin, indicating that PGs are responsible for exudate formation at the early phase of pleurisy. Pleural exudation at 1 to 5 h in IP, EP2, or EP3 knockout mice, but not in EP1 and EP4 knockout, was significantly reduced compared with in WT mice. In the exudates, 6-keto- PGF(1)alpha and PGE(2) were detected as the major PGs, each with its peak concentration at 3 h. In addition, involvement of bradykinin in the phenomenon was suggested by the fact that captopril, a kininase inhibitor, enhanced the exudate formation and increased the amount of 6-keto- PGF(1)alpha and PGE(2) and that a bradykinin B2-receptor antagonist inhibited the exudate formation. In contrast, leukocyte migration into pleural cavity was not influenced by indomethacin-treatment nor by these receptor deficiencies. These results demonstrate participation of EP2 and EP3 along with IP in pleural exudate formation but not in leukocyte migration in carrageenin-induced mouse pleurisy.

DOI： 10.1124/jpet.104.071548

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL INVESTIGATION INC  

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the reninangiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI(2) in renovascular hypertension in vivo, employing mice lacking the PGI(2) receptor (IP-/- mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP-/- mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP-/- mice than in WT mice. All these parameters were measured in mice lacking the four PGE(2) receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI(2) is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP-/- mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP-/- mice. These results indicate that PGI(2) derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.

DOI： 10.1172/JCI200421382

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background - In the heart with acute myocardial infarction, production of prostaglandin (PG) E-2 increases significantly. In addition, several subtypes of PGE(2) receptors (EPs) have been reported to be expressed in the heart. The role of PGE(2) in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE(2) via EP4, an EP subtype, in I/R injury using mice lacking EP4 (EP4-/- mice).
Methods and Results - In murine cardiac ventricle, competitive reverse transcription - polymerase chain reaction revealed the highest expression level of EP4 mRNA among EP mRNAs. EP4-/- mice had larger infarct size than wild-type mice in a model of I/R; the left anterior descending coronary artery was occluded for 1 hour, followed by 24 hours of reperfusion. In addition, isolated EP4-/- hearts perfused according to the Langendorff technique had greater functional and biochemical derangements in response to I/R than wild-type hearts. In vitro, AE1-329, an EP4 agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP4 agonist, was administered 1 hour before coronary occlusion, it reduced infarct size significantly in wild-type mice. Notably, a similar cardioprotective effect was observed even when it was administered 50 minutes after coronary occlusion.
Conclusions - Both endogenous PGE(2) and an exogenous EP4 agonist protect the heart from I/R injury via EP4. The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.

DOI： 10.1161/01.CIR.0000128046.54681.97

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background-Circulatory failure in sepsis arises from vascular hyporesponsiveness, in which nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. Details of the cross talk between thromboxane (TX) A(2) and the iNOS-NO system, however, remain unknown. We intended to clarify the role of TXA(2), via the cross talk, in vascular hyporesponsiveness.
Methods and Results-We examined cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) and cytokine-induced hyporesponsiveness of the aorta from mice lacking the TXA(2) receptor (TP-/- mice). The cytokine-induced iNOS expression and NO production observed in wild-type VSMCs were significantly augmented in TP-/- VSMCs, indicating an inhibitory effect of endogenous TXA2 on iNOS expression. Furthermore, in indomethacin-treated wild-type VSMCs, U-46619, a TP agonist, inhibited cytokine-induced iNOS expression and NO production in a concentration-dependent manner, effects absent from TP-/- VSMCs. In an ex vivo system, the cytokine-induced hyporesponsiveness of aortas to phenylephrine was significantly augmented in TP-/- aorta but was almost completely canceled by aminoguanidine, an iNOS inhibitor. Accordingly, cytokine-induced NO production was significantly higher in TP-/- aorta than in wild-type aorta. Moreover, U-46619 significantly suppressed lipopolysaccharide-induced NO production in vivo only in wild-type mice.
Conclusions-These results suggest that TXA(2) has a protective role against the development of vascular hyporesponsiveness via its inhibitory action on the iNOS-NO system under pathological conditions such as sepsis.

DOI： 10.1161/01.CIR.0000093194.21109.EC

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

プロスタノイドは,プロスタグランジン(PG)とトロンボキサン(TX)より成り,これらは標的細胞表面にある各プロスタノイドに特異的な受容体を介して,多彩な生理作用を発揮する.現在,PGD2,PGE2,PGF2α,PGI2,TXA2の受容体として,各々DP,EP,FP,IP,TPが知られており,EPはEP1,EP2,EP3,EP4の4種類のサブタイプに分類されている.これらのプロスタノイド受容体を欠損するマウスを用いて,心血管系におけるプロスタノイドの病態生理的役割を解析した結果,以下の点が明らかとなった.PGI2は虚血心筋保護,圧負荷心肥大の抑制及び腎血管性高血圧の進展に役割を果たしている.PGE2は,EP3とEP4を介して虚血心筋保護に,またEP3を介して血小板凝集反応を増強し止血や血栓形成に関与する.PGF2αとTXA2は,共に炎症急性期の頻拍を仲介する

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DOI： 10.1042/CS103S210S

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

1 Effects of the prostanoids on the growth of cultured aortic vascular smooth muscle cells (VSMCs) were examined using mice lacking prostanoid receptors.
2 Proliferation of VSMCs was assessed by measuring [H-3]-thymidine incorporation and the cell number, and their hypertrophy by [C-14]-leucine incorporation and protein content.
3 In VSMCs from wild-type mice, expressions of mRNAs for the EP4 and TP were most abundant, followed by those for the IP, EP3 and FP, when examined by competitive reverse transcriptase-PCR. Those for the EP1, EP2 and DP, however, could not be detected.
4 AE1-329, an EP4 agonist, and cicaprost, an IP agonist, inhibited platelet derived growth factor proliferation of VSMCs from wild-type mice; these inhibitory effects disappeared completely in VSMCs from EP4-/- and IP-/- mice, respectively. In accordance with these effects, AE1-329 and cicaprost stimulated cAMP production in VSMCs from wild-type mice, which were absent in VSMCs from EP4-/- and IP-/- mice, respectively.
5 Effects of PGE(2) on cell proliferation and adenylate cyclase were almost similar with those of AE1-329 in VSMCs from wild-type mice, which disappeared in VSMCs from EP4-/- mice.
6 PGD(2) inhibited PDGF-induced proliferation of VSMCs from both wild-type and DP-/- mice to a similar extent. This action of PGD(2) was also observed in VSMCs from EP4(-/-) and IP-/- mice.
7 In VSMCs from wild-type mice, I-BOP, a TP agonist, showed potentiation of PDGF-induced hypertrophy. I-BOP failed to show this action in VSMCs from TP-/- mice.
8 The specific agonists for the EP1, EP2 or EP3, and PGF(2)alpha showed little effect on the growth of VSMCS.
9 These results show that PGE(2), PGI(2) and TXA(2) modulate PDGF-induced proliferation or hypertrophy of VSMCs via the EP4, IP and TP, respectively, and that the inhibitory effect of PGD(2) on PDGF-induced proliferation is not mediated by the DP, EP4 or IP.

DOI： 10.1038/sj.bjp.0704749

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

In chronic heart failure and acute myocardial infarction, the tissue level of endothelin (ET)-1 in the heart, as well as its plasma level, has been reported to increase markedly. There is, however, little information about what in these pathologic conditions leads to increased production of ET-1, and which type of cell in the heart produces ET-1. We examined the mRNA and peptide expression of ET-1 using cultured rat neonatal cardiomyocytes, in which mitochondrial dysfunction was induced by rotenone, a mitochondrial respiratory chain complex I inhibitor. because one of the common features in failing or ischemic hearts is an alteration in energy metabolism due to mitochondrial dysfunction. Rotenone increased glucose use by the culture cells within 12 h of addition without affecting cell viability, and depressed the mitochondrial membrane potential after 72 h, indicating the induction of mitochondrial dysfunction in cardiomyocytes. Rotenone induced significant increase in the expression level of mRNA for ET-1 within 1 h of addition. In accordance with this finding, immunoreactive ET-1 in culture medium increased 3 times after 24 h of incubation, suggesting active secretion of ET-1 from cultured cells treated with rotenone. Immunocytochemical analysis verified significant increase of ET-1 peptide in cardiomyocytes, confirming the production of ET-1 by cardiomyocytes. These results suggest that derangement of mitochondrial function in cardiomyocytes itself could lead to the increased production of ET-1 in cardiomyocytes, and that this mechanism may contribute to the increased production of ET-1 in failing and ischemic hearts.

DOI： 10.1097/00005344-200112000-00006

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

To understand the pathophysiological role of endothelin-1 in the failing heart, we constructed a cellular mitochondrial impairment model and demonstrated the effect of endothelin-1. Primary cultured cardiomyocytes from neonatal rats were pretreated with rotenone, a mitochondrial complex I inhibitor, and the cytotoxic effect of endothelin-1 on the cardiomyocytes was demonstrated. Rotenone gradually decreased the pH of the culture medium with incubation time and caused slight cell injury. Endothelin-1 markedly enhanced the effect of rotenone that decreased the pH of the medium and enhanced cellular injury: The enhancement of the decrease in pH and cell injury induced by endothelin-1 was counteracted by the endothelin ETA receptor antagonist BQ123 or by :maintaining the pH of the medium by the addition of 50 mM HEPES. Endothelin-1 markedly increased the uptake of 2-deoxyglucose and lactic acid production when the cardiomyocytes were pretreated with rotenone. These findings suggest that the stimulation of glucose uptake and anaerobic glycolysis followed by the increase in lactic acid accumulation in cardiomyocytes under the condition of mitochondrial impairment may be involved, at least in part, in the cellular injury by endothelin-1. Moreover, these findings suggest the possibility that the effect of endothelin-1 on myocardium is reversed by the condition of the mitochondria; and endogenous endothelin-1 may deteriorate cardiac failure with mitochondrial dysfunction. This may contribute to clarify the beneficial effect of endothelin receptor blockade in improving heart failures. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0014-2999(01)01434-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background-Prostaglandin (PG) I-2 and thromboxane (TX) A(2), the most common prostanoids in the cardiovascular system, are produced abundantly during cardiac ischemia/reperfusion (I/R); their roles in I/R injury, however, remain undetermined. We intended to clarify these roles of PGI(2) and TXA(2) using mice lacking the PGI, receptor, IP-/- mice, or the TXA(2) receptor, TP-/- mice.
Methods and Results-The left anterior descending coronary artery was occluded for 1 hour and then reperfused for 24 hours. The size of myocardial infarct in IP-/- mice was significantly larger than that in wild-type mice, although the size of the area at risk was similar between the 2 groups of mice. In contrast, there was no such difference between TP-/- and wild-type mice. To further determine whether PGI(2) and TXA(2) act directly on the cardiac tissue or indirectly through their action on blood constituents, we perfused excised heart according to the Langendorff technique. The isolated heart was then subjected to global ischemia followed by reperfusion. In IP-/- mice, developed tension and coronary flow rate during reperfusion were significantly lower and release of creatine kinase was significantly higher than those in wild-type mice. There were no such differences, however, between TP-/- and wild-type mice.
Conclusions-PGI(2), which was produced endogenously during cardiac I/R, exerts a protective effect on cardiomyocytes independent of its effects on platelets and neutrophils. In contrast, TXA(2) has little role in the cardiac I/R injury.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Diesel exhaust particles cause an impairment of endothelium-dependent vasorelaxation and are associated with cardiopulmonary-related diseases and mortality, but the mechanistic details are poorly understood. Since we reported previously that phenanthraquinone, an environmental chemical contained in diesel exhaust particles, suppresses neuronal nitric oxide synthase (nNOS) activity by shunting electrons away from the normal catalytic pathway, it was hypothesized that phenanthraquinone inhibits endothelial NOS (eNOS) activity and affects vascular tone. Therefore, the effects of phenanthraquinone on eNOS activity, endothelium-dependent relaxation, and blood pressure were examined in the present study. Phenanthraquinone inhibited NO formation evaluated by citrulline formed by total membrane fraction of bovine aortic endothelial cells with an IC50 value of 0.6 muM. A kinetic study revealed that phenanthraquinone is a competitive inhibitor with respect to NADPH and a noncompetitive inhibitor with respect to L-arginine. Endothelium-dependent relaxation of rat aortic rings by ACh was significantly inhibited by phenanthraquinone (5 muM), whereas the endothelium-independent relaxation by nitroglycerin was not. Furthermore, an intraperitoneal injection of phenanthraquinone (0.36 mmol/ kg) to rats resulted in an elevation of blood pressure (1.4-fold, P < 0.01); under this condition, plasma levels of stable NO metabolites, nitrite/nitrate, in phenanthraquinone-treated rats was reduced to 68% of control levels. The present findings suggest that phenanthraquinone has a potent inhibitory action on eNOS activity via a similar mechanism reported for nNOS, thereby causing the suppression of NO-mediated vasorelaxation and elevation of blood pressure.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background-Hypoxia-inducible factor (HIF)-1 alpha is an important transcriptional factor that activates the gene expression of glycolytic enzymes, which are activated as compensation for impaired beta -oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expression is markedly increased in heart failure. The mechanism, however, is unknown. Because we found an HIF-1 alpha binding site in the 5 ' -promoter region of the ET-1 gene, we hypothesized that HIF-1 alpha is involved in this mechanism.
Methods and Results-In rat cardiomyocytes, luciferase assay and electrophoretic mobility shift assay showed that HIF-1 alpha transcriptionally activates ET-1 gene expression by direct interaction with the predicted DNA binding site in the 5 ' -promoter region. HIF-1 alpha mRNA and ET-1 mRNA in the failing heart increased during the aggravation of heart failure in vivo in animal models, ie, rats with myocardial infarction and hamsters with cardiomyopathy. In cultured cardiomyocytes treated with a mitochondrial inhibitor, HIF-1 alpha mRNA and ET-1 mRNA were markedly increased with activated glycolysis, and antisense oligonucleotide for HIF-1 alpha largely inhibited the increased gene expression of ET-1.
Conclusions-The present study revealed a novel molecular mechanism of upregulation of myocardial ET-1 in heart failure, indicating that induction of HIF-1 alpha to stimulate glycolysis as an adaptation in heart failure against impaired energy metabolism alternatively causes an elevation of cardiac ET-1 gene expression as a maladaptation.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

To know which receptors of prostaglandins are involved in the regulation of TNF alpha and interleukin 10 (IL-10) production, we examined the production of these cytokines in murine peritoneal macrophages stimulated with zymosan. The presence of PGE, or the PGI, analog carbacyclin in the medium reduced the TNF alpha production to one-half, whereas IL-10 production increased several fold; and indomethacin caused the reverse effects, suggesting that endogenous prostaglandins may have a regulatory effect on the cytokine production. Among prostaglandin E (EP) receptor-selective synthetic agonists, EP2 and EP4 agonists caused down-regulation of the zymosan-induced TNF alpha production, but up-regulation on the IL-IO production; while EP1 and EP3 agonists showed no effect. Macrophages harvested from prostaglandin I (IP) receptor-deficient mice showed the up- and down-regulatory effects on the cytokine production by the EP2 and EP4 agonists or PGE(2), but no effect was obtained by carbacyclin. On the contrary, macrophages from EP2-deficient mice showed the effect by PGE(2), carbacyclin, and the EP4 agonist, but not by the EP2 agonist; and the cells from EP4-deficient mice showed the effect by PGE,, carbacyclin, and EP2 agonist, but not by the EP3 agonist. These functional effects of prostaglandins well accorded with the mRNA expression of TNF alpha and IL-10 when such expression was examined by the RT-PCR method. The peritoneal macrophages from normal mice expressed IF, EP2, and EP4 receptors, but not EPI and EP3, when examined by RT-PCR. Thus the results suggest that PGI, and PGE, generated simultaneously with cytokines by macrophages treated with zymosan may influence the cytokine production through IF, EP2, and EP4 receptors. (C) 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0006-2952(01)00586-X

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/00005344-200036051-00041

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/00005344-200036051-00061

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Cardiac myocytes produce nitric oxide (NO). We studied the effects of intense exercise on the expression of NO synthase (NOS) and the tissue level of nitrite (NO2-)/nitrate (NO3-) (i.e., NOx), which are stable end products of NO in the heart. Rats ran on a treadmill for 45 min. Immediately after this exercise, the heart was quickly removed. Control rats remained at rest during the same 45-min period. The mRNA level of endothelial NOS (eNOS) in the heart was markedly lower in the exercised rats than in the control rats. Western blot analysis confirmed downregulation of eNOS protein in the heart after exercise. Tissue NOx level in the heart was significantly lower in the exercised rats than in the control rats. The present study revealed for the first time that production of NO in the heart is decreased by intense exercise. Because NO attenuates positive inotropic and chronotropic responses to beta(1)-adrenergic stimulation in the heart, the decrease in cardiac production of NO by intense exercise may contribute to the acceleration of increase in myocardial contractility and heart rate during intense exercise.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Prolonged exposure to arsenic results in peripheral and cardiovascular manifestations, as does impaired production of endothelial nitric oxide (NO). In vitro studies have indicated that endothelial cells undergo damage by arsenic. However, no information has been available on the relationship between NO synthesis and chronic arsenic poisoning in humans. The present study was designed to reveal this question. The subjects were 33 habitants who continued to drink well water containing high concentrations of inorganic arsenic (mean value = 0.41 mu g/ml) for about 18 years in Inner Mongolia, China, and 10 other people who lived in this area but exposed to minimal concentrations of arsenic (mean value = 0.02 mu g/ml) were employed as controls. Mean blood concentration of total arsenic was six times higher in exposed subjects than controls; 42.1 vs. 7.3 ng/ml, p <.001. Mean serum concentration of nitrite/nitrate, stable metabolites of endogenous NO, was lower in arsenic-exposed subjects than in controls: 24.7 vs. 51.6 mu M, p < .001. In total samples, an inverse correlation with serum nitrite/nitrate levels was strong for blood inorganic arsenic (r = -0.52, p < .001) and less strong for its metabolites, monomethyl arsenic (r = -0.45, p < .005) and dimethyl arsenic (r = -0.37, p < .05). Furthermore, serum nitrite/nitrate concentration was significantly correlated with nonprotein sulfhydryl level in whole blood (r = 0.58, p < .001). In an in vitro study, we demonstrated that inorganic arsenite or arsenate suppresses the activity of endothelial NO synthase in human umbilical vein endothelial cells. These results suggest that long-term exposure to arsenic by drinking well water possibly reduces NO production in endothelial cells, resulting in a decrease in reduced nitrite/nitrate concentrations. Peripheral vascular disorders caused by arsenic may be attributable in part to impairment of NO production in vivo. (C) 2000 Elsevier Science Inc.

DOI： 10.1016/S0891-5849(00)00209-4

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Lippincott Williams and Wilkins  

We have reported that the expression of endothelin-1 (ET-1) increases in the failing heart. With the progress of heart failure, it has been reported that energy metabolism switches from mitochondrial b-oxidation to glycolysis. Furthermore, it has been reported that apoptosis is induced in the failing heart. However, it is not known how the gene expression of preproendothelin-1 and cellular apoptosis are affected by the mitochondrial dysfunction. Therefore, in order to elucidate this problem, we developed an in vitro model of mitochondrial dysfunction using rotenone, a mitochondrial respiratory chain complex I inhibitor, and studied preproendothelin-1 gene expression and apoptosis. Rotenone greatly increased the gene expression of preproendothelin-1 in cardiomyocytes. This result suggests that the gene expression of preproendothelin-1 is induced by the mitochondrial dysfunction. Furthermore, treatment of cardiomyocytes with rotenone induced an elevation of caspase-3 activity, and caused a marked increase in DNA laddering, an indication of apoptosis. In conclusion, it is suggested that mitochondrial impairment in primary cultured cardiomyocytes induced by rotenone in vitro, mimics some of the pathophysiological features of heart failure in vivo, and that ET-1 may have a role in myocardial dysfunction with impairment of mitochondria in the failing heart.

DOI： 10.1097/00005344-200036001-00101

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Japan  

To neutralize the toxicity of verotoxin (VT) produced by Escherichia coli type O-157, a soluble pseudo-receptor (Lyso Gb3) was synthesized with the deacylated form of the natural receptor, globotrisylceramide (Galα 1- 4Galβ1-4-glucosylceramide
Gb3). In this study, we evaluated the characteristics and pharmacological effects of Lyso Gb3, using VT2. It was confirmed that Lyso Gb3 specifically recognized VT2. Lyso Gb3 itself had little influence on the in-vitro growth of Vero cells, but markedly augmented VT2-induced cytotoxicity. In addition, the VT2-induced killing of mice was not decreased, but was, rather, increased by Lyso Gb3. These results indicate that the soluble pseudo-receptor Lyso Gb3 recognized VT2. However, it did not reduce, but, rather, enhanced, VT2-induced toxicity in the presence of the natural receptor, although Lyso Gb3 alone had no toxicity.

DOI： 10.1007/s101560050044

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

We and other groups have reported that endothelin (ET) -1 expression in the heart is altered in the setting of heart diseases. We have also reported that myocardial ET-I is involved in the progression of heart failure, and that an ET receptor antagonist improves long-term survival in heart failure (Nature 384: 353-355, 1996). However, the role of myocardial ET-2 in disease states are not known. To characterize the role of ET-2, we used a) the failing hearts of rats with heart failure caused by myocardial infarction, and b) primary cultured cardiomyocytes subjected to hypoxia. In the failing heart in vivo, ET-1 mRNA increased by 390% compared with that in the non-failing heart, while ET-2 mRNA drastically decreased by 88%. Thus, gene expression of ET1 and ET-2 was reciprocally altered in the failing heart in vivo. In in vitro studies, reciprocal alterations in ET-1 and ET-2 gene expression were also observed in isolated primary cultured cardiomyocytes, subjected to hypoxia. Specifically, acute hypoxic stress induced a significant increase (360% of the basal level) in ET-2 mRNA expression compared with that in normoxic cells, whereas it decreased ET-1 mRNA expression by 62% in primary cultured cardiomyocytes. Although these two crucial conditions, i.e., heart failure in vivo and acute hypoxic stress in vitro, are pathophysiologically distinct from each other, reciprocal alteration of ET-1 and ET-2 gene expression was observed in both cases. To further investigate the regulatory mechanism of the altered gene expression, luciferase analysis was performed using primary cultured cardiomyocytes. ET-2 promoter, which is the 5'-flanking region of preproET-2 gene (5'ET-2), showed a marked increase in luciferase activity during acute hypoxia. In contrast, the luciferase activity of 5'ET-1 (ET-1 promoter) did not change in response to hypoxic stress. The present study suggests that there are transcriptionally distinct regulatory mechanisms for ET-1 and ET-2 expression in cardiomyocytes, and therefore this study may provide a new aspect of cardiac ET system that not only ET-I but also ET-2 can be participated in the pathophysiological conditions.

DOI： 10.1016/S0024-3205(99)00416-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Academic Press Inc.  

A170 is an oxidative stress inducible protein having a Zinc finger domain, two PEST sequences, and many potential phosphorylation sites for serine/threonine kinases. These structural features suggest that the phosphorylation of A170 affects its function and degradation. We have found that A170 is phosphorylated in cultured murine peritoneal macrophages. In addition, using recombinant A170 proteins, we found two proteins of 40 and 44 kDa with kinase activity in cell extracts using an in-gel kinase assay. We compared the properties of the intrinsic A170 kinases with those of mitogen-activated protein kinase (ERK 2), protein kinase A (PKA), casein kinase II (CK II), and protein kinase C, since their catalytic subunits have molecular masses similar to A170 kinases. ERK 2, CK II, and PKA phosphorylated recombinant A170 as a substrate. The 40 and 44 kDa kinases present in the macrophage extract were similar to α and α' subunits of CK II in respect to substrate specificity, pharmacological properties, immuno-reactivities, and ubiquitous expression in tissues.

DOI： 10.1006/bbrc.1997.7783

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DOI： 10.1006/bbrc.1997.6221

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

Using differential screening we have cloned a cDNA encoding a novel oxidative stress protein designated A170 from murine peritoneal macrophages. It has a Zn-finger domain, a PEST domain and several potential phosphorylation sites for kinases. Treatments with oxidative stress agents such as diethyl maleate and paraquat increased a 2.0-kilobase A170 mRNA about twofold in the macrophages after 12 hours in culture. However, H2O2 or glucose/glucose oxidase did not increase the level of the A170 mRNA. Using an A170-specific antibody we have detected in the macropha,ges a 60-kDa protein that was induced 5 to 10 hours after the addition of the oxidative stress agents. A search of sequence databases revealed that the A170 protein is roughly 90% identical to a human protein that binds to the Src homology 2 domain of the T-cell-specific tyrosine kinase p561(kck). These features suggest that the A170 protein plays a significant role in oxidative stress-responsive signal transduction in macrophages. (C) 1996 Academic Press, Inc.

DOI： 10.1006/bbrc.1996.1377

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

炎症は、生体の防御反応であるが、慢性炎症においては、炎症部位で筋線維芽細胞の産生する細胞外マトリックス蓄積による臓器線維化が起こる。一方、急性炎症のメディエーターと考えられてきたプロスタノイドは、近年、臓器線維化においても様々な役割を果たしていることが明らかとなってきた。本稿では、肺、腎臓、心臓、肝臓に焦点を当て、各臓器の線維化におけるプロスタノイドの役割について、最近の知見を紹介した。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)医学書院  

プロスタノイド,ロイコトリエン,リポキシンを含むエイコサノイドは,ω-6必須脂肪酸の酸化によって生成される生理活性脂質である.内因性に産生されたエイコサノイドは,炎症や組織の恒常性維持において中心的な役割を果たしている.エイコサノイドは,急性炎症のメディエーターとして広く知られていたが,現在,炎症の初期過程から収束過程までの全般にわたり様々な作用を発揮していることが明らかとなっている.本稿では,炎症過程におけるエイコサノイドの役割について概説する.(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J01205&link_issn=&doc_id=20110119220053&doc_link_id=%2Fag6niria%2F2011%2F0069s1%2F054%2F0331-0335%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2011%2F0069s1%2F054%2F0331-0335%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：先端医学社  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

1992年のノーベル生理学・医学賞は、「生体制御機構としての可逆的蛋白質リン酸化の発見」に対して、Edmond H.Fischer博士とEdwin G.Krebs博士へ、1994年のノーベル生理学・医学賞は、「G蛋白質およびそれらの細胞内情報伝達における役割の発見」に対して、Alfred G.Gilman博士とMartin Rodbell博士へ贈られた。どちらも細胞内情報伝達機構を解析するために非常に重要なメカニズムであり、現在も盛んに研究がおこなわれており、日々新たな知見が得られている分野である。本稿では、各受賞者の経歴や発見に至るまでの経緯について概説する。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J01205&link_issn=&doc_id=20100722300005&doc_link_id=%2Fag6niria%2F2010%2F0068s7%2F006%2F0029-0032%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2010%2F0068s7%2F006%2F0029-0032%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(株)日本臨床社  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J01205&link_issn=&doc_id=20100722300003&doc_link_id=%2Fag6niria%2F2010%2F0068s7%2F004%2F0020-0024%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2010%2F0068s7%2F004%2F0020-0024%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：医歯薬出版  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：日本臨床社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：メディカルレビュー社  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：日本語   掲載種別：書評論文，書評，文献紹介等  

Scopus

PubMed

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：最新医学社  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

DOI： 10.1152/ajpregu.00019.2006

Web of Science

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：医歯薬出版  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：医学書院  

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記述言語：英語   出版者・発行元：MEDIMOND S R L  

We intended to clarify the role of prostaglandin (PG) E-2 in cardiac ischemia-reperfusion (I/R) injury. Mice lacking EP4 (EP4-KO mice) had a larger infarct size than wild-type mice in a model of I/R injury. In addition, isolated EP4-KO hearts perfused according to the Langendorff technique had greater creatine kinase release in response to I/R than wild-type hearts. In vitro, AE1-329, an EP4 agonist, raised cAMP concentration remarkably in non-cardiomyocytes, while the action was weak in cardiomyocytes. ONO-4819, another EP4 agonist shows a potent cardioprotective effect not only when injected before ischemia but also when injected after ischemia in I/R injury in vivo. Potent cardio-protective effect of ONO-4819 suggests that the compound would be useful for treatment of acute myocardial infarction.

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   出版者・発行元：MEDIMOND S R L  

The present study was designed to clarify the action of thromboxane (TX) A(2) on the inducible nitric oxide synthase (iNOS)-NO system and to evaluate its role in the regulation of vascular tone under septic conditions. Cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) were significantly augmented in mice lacking TXA(2) receptor (TP-KO) over that in wild-type (WT) mice. U-46619, a TP agonist, inhibited cytokine-induced iNOS expression. The cytokine-induced aortic hyporesponsiveness to phenylephrine was significantly augmented in TP-KO. In in vivo septic model, elevated plasma NO level was significantly decreased by administrating U-46619. These results suggest that TXA(2) regulates vascular tone under septic conditions via the inhibitory effect on the expression of iNOS.

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

プロスタノイドは,プロスタグランジン(PG)とトロンボキサン(TX)よりなる生理活性脂質であり,生体においてさまざまな作用を発揮する.また,その作用は各々のプロスタノイドに特異的な受容体を介して発揮される.一方,これらの受容体は,心血管系に広く発現している.また,プロスタノイドの産生は,心血管系でのさまざまな病態に伴い亢進することが知られている.本稿では,各プロスタノイド受容体欠損マウスを用いた解析から明らかとなった,プロスタノイドの心虚血・再灌流障害,圧負荷心肥大,炎症性頻脈,動脈硬化,腎血管性高血圧,炎症時の血管緊張維持や血小板機能調節における新規役割について紹介する(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

DOI： 10.1254/fpj.123.5

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

DOI： 10.1254/fpj.123.5

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

DOI： 10.1161/01.CIR.0000093194.21109.EC

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

DOI： 10.1161/01.CIR.0000093194.21109.EC

Web of Science

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：日本心脈管作動物質学会  

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

We examined the roles of prostaglandin receptors regulating tumor necrosis factor-alpha (TNFalpha) and IL-10 production by zymosan-stimulated murine peritoneal macrophages. During the stimulation with zymosan for 5 h, the presence of PGE(2) or carbacyclin suppressed the TNFa. production, whereas it increased that of IL-10; and indomethacin caused the reverse effects, suggesting that endogenous prostaglandins may have regulatory effects on the cytokine production. Among the EP subtype-selective synthetic agonists used, EP2 and EN agonists caused down-regulation of the TNFa production, but up-regulation of the IL-10 production; whereas EP1 and EP3 agonists showed no effect. Macrophages harvested from IP, EP2 or EN receptor-deficient mice lacked the up- and down-regulatory effects on the cytokine production by each corresponding agonist. These effects of prostaglandins agreed well with the mRNA expression of TNFalpha and IL-10 when mRNA levels were examined by the RT-PCR method. Thus, the results suggest that endogenous PGI(2) and PGE(2) may exert their anti-inflammatory influence on the cytokine production through IP, EP2, and EN receptors. (C) 2002 Elsevier Science B.V. All rights reserved.

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：日本語   出版者・発行元：現代医療社  

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記述言語：日本語   出版者・発行元：社団法人日本循環器学会  

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記述言語：日本語   出版者・発行元：丸善(株)  

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記述言語：日本語   出版者・発行元：社団法人日本循環器学会  

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開催年月日： 2017年3月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：長崎  

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開催年月日： 2016年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：札幌  

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開催年月日： 2016年3月

記述言語：英語   会議種別：ポスター発表  

開催地：横浜市  

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開催年月日： 2016年2月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：徳島  

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開催年月日： 2015年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：富山市  

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開催年月日： 2015年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：富山市  

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開催年月日： 2015年5月

記述言語：英語   会議種別：ポスター発表  

開催地：Washington, D.C.  

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開催年月日： 2015年3月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：名古屋  

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開催年月日： 2015年3月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋  

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開催年月日： 2014年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：山形  

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開催年月日： 2014年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福島  

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開催年月日： 2014年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福島市  

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開催年月日： 2014年5月

記述言語：英語   会議種別：ポスター発表  

開催地：Chicago  

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開催年月日： 2014年3月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：仙台  

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開催年月日： 2014年3月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：仙台  

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開催年月日： 2014年

記述言語：英語  

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開催年月日： 2014年

記述言語：英語  

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開催年月日： 2013年5月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Orlando  

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開催年月日： 2013年3月

記述言語：英語   会議種別：ポスター発表  

開催地：福岡  

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開催年月日： 2013年3月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：福岡  

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開催年月日： 2013年2月

記述言語：英語   会議種別：ポスター発表  

開催地：東京  

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開催年月日： 2013年1月

記述言語：日本語  

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開催年月日： 2013年

記述言語：英語  

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開催年月日： 2013年

記述言語：英語  

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開催年月日： 2012年1月

記述言語：日本語  

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開催年月日： 2012年1月

記述言語：日本語  

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開催年月日： 2012年

記述言語：英語  

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開催年月日： 2011年5月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2006年3月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：横浜  

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開催年月日： 2005年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：CANADA  

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開催年月日： 2005年3月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：横浜  

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開催年月日： 1999年3月

記述言語：日本語  

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開催年月日： 1998年2月

記述言語：日本語  

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