Faculty Profiles - OTSUKA Fumio

Papers - OTSUKA Fumio

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2型糖尿病初期治療における経口糖尿病降下薬の処方選択基準に関するアルゴリズムの作成と有用性の検討 Reviewed

塩見明日香、三好智子、村上和敏、水島孝明、黒田真生、尾上洋、相良英憲、座間味義人、大塚文男、名倉弘哲

ライフ・サイエンスProgress in Medicine 33 ( 10 ) 2261 - 2268 2013.10

Language：Japanese Publisher：(株)ライフ・サイエンス

薬理作用の異なる薬剤が多数処方される2型糖尿病治療域において、ガイドラインを適切に理解し薬剤の適正使用を行うことは、臨床経験の少ない研修医や新人薬剤師にとっては困難であり、煩雑な知識を要する。そこで、2型糖尿病初期治療の選択基準となるアルゴリズムを糖尿病診療ガイドラインなどに基づき作成し、その有効性について研修医、総合内科医師、薬剤師にアンケートを実施した。アルゴリズムの有用性に関する評価では、研修医と総合内科医師の間で有意差は認められなかった。一方、薬剤師では、「本アルゴリズムの使用により、医師の処方意図や患者背景について考えるきっかけとなりましたか」との質問に対して、経験年数が6年以上の薬剤師の値に比べ、経験年数が1〜5年の薬剤師の方が有意に高い値を示した。したがって、アルゴリズムを作成し治療選択基準を図式化することで、経験年数の少ない薬剤師の迅速な理解向上に寄与できることが示唆された。(著者抄録)

Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells. Reviewed International journal

Naoko Tsukamoto, Fumio Otsuka, Kanako Ogura-Ochi, Kenichi Inagaki, Eri Nakamura, Kishio Toma, Tomohiro Terasaka, Yasumasa Iwasaki, Hirofumi Makino

Molecular and cellular endocrinology 375 ( 1-2 ) 1 - 9 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The role of melatonin, a regulator of circadian rhythm, in adrenocorticotropin (ACTH) production by corticotrope cells has not been elucidated. In this study, we investigated the effect of melatonin on ACTH production in relation to the biological activity of bone morphogenetic protein (BMP)-4 using mouse corticotrope AtT20 cells that express melatonin type-1 (MT1R) but not type-2 (MT2R) receptors. We previously reported that BMP-4 inhibits corticotropin-releasing hormone (CRH)-induced ACTH production and proopiomelanocortin (POMC) transcription by inhibiting MAPK signaling. Both melatonin and an MT1R/MT2R agonist, ramelteon, suppressed CRH-induced ACTH production, POMC transcription and cAMP synthesis. The inhibitory effects of ramelteon on basal and CRH-induced POMC mRNA and ACTH levels were more potent than those of melatonin. Treatment with melatonin or ramelteon in combination with BMP-4 additively suppressed CRH-induced ACTH production. Of note, the level of MT1R expression was upregulated by BMP-4 stimulation. The suppressive effects of melatonin and ramelteon on POMC transcription and cAMP synthesis induced by CRH were not affected by an MT2R antagonist, luzindole. On the other hand, BMP-4-induced Smad1/5/8 phosphorylation and the expression of a BMP target gene, Id-1, were augmented in the presence of melatonin and ramelteon. Considering that the expression levels of BMP receptors, ALK-3/BMPRII, were increased by ramelteon, MT1R action may play an enhancing role in BMP-receptor signaling. Among the MT1R signaling pathways including AKT, ERK and JNK pathways, inhibition of AKT signaling functionally reversed the MT1R effects on both CRH-induced POMC transcription and BMP-4-induced Id-1 transcription. Collectively, MT1R signaling and BMP-4 actions were mutually augmented, leading to fine-tuning of ACTH production by corticotrope cells.

DOI： 10.1016/j.mce.2013.05.010

Systemic varicella-zoster virus infection in two critically ill patients in an intensive care unit. Reviewed International journal

Hideharu Hagiya, Maya Kimura, Toru Miyamoto, Fumio Otsuka

Virology journal 10 225 - 225 2013.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BMC

Varicella-zoster virus (VZV) usually causes localized zoster in adults. However, in immunocompromised patients, it can cause systemic infection accompanied by complications such as pneumonia, encephalitis, and hepatitis. Although most of critically ill patients in intensive care unit (ICU) are immunologically compromised, they are usually not considered to be at risk for systemic VZV infection.We report two cases of systemic VZV infection occurring in critically ill patients in an ICU. One patient was a 69-year-old man with Streptococcus pneumoniae-induced purpurafulminans, and the other was a 75-year-old woman with severe acute pancreatitis. During the clinical course in the ICU, characteristic vesicles with umbilical fossa appeared diffusely and bilaterally on their face, trunk, and extremities. VZV-specific IgG levels were confirmed to be elevated compared to that of the pre-onset, and a diagnosis of recurrent VZV infection was made in both patients. The patients were treated at the same ICU but did not coincide with each other; therefore a cross-infection was unlikely. They were treated with intravenous acyclovir, but the latter patient eventually died of respiratory failure.VZV infection can cause a number of serious complications, and can lead to death in some patients. Early detection and proper treatment are needed to prevent the infection from spreading out and save the patients. It might be necessary to consider antiviral prophylaxis against VZV infection for a part of critically ill patients in ICU, although the effectiveness of this approach is yet to be established.

DOI： 10.1186/1743-422X-10-225

Erdheim-Chester病が強く疑われた下垂体機能低下症の一例 Reviewed

三好智子、大塚文男、稲垣兼一、田中康司、越智可奈子、藤井一恭、藤井伸治、当真貴志雄、中村絵里、塚本尚子、武田昌也、三村由香里、小倉俊郎、景山甚郷、槇野博史

日本内分泌学会雑誌 89 ( suppl ) 21 - 23 2013.6

GRK-6 mediates FSH action synergistically enhanced by estrogen and the oocyte in rat granulosa cells. Reviewed International journal

Tomoko Miyoshi, Fumio Otsuka, Shunichi Shimasaki

Biochemical and biophysical research communications 434 ( 2 ) 401 - 6 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Estrogen is known to play a pivotal role in granulosa cell responses to follicle-stimulating hormone (FSH) that is critical for the establishment of dominant follicles and subsequent ovulation in mammals. Thus, elucidating the cellular and molecular mechanisms that regulate FSH activity is important to understand female fertility. We previously discovered that the oocyte is required for estrogen to exert its positive effects on FSH activity in rat granulosa cells. This finding supports the new concept that estrogen action in granulosa cells is mediated by the oocyte. In the current study, we explored the underlying mechanism. In the presence of oocytes, estrogens enhanced FSH-induced increases in aromatase, steroidogenic acute regulatory protein and FSH receptor mRNA expression as well as cAMP production. However, as forskolin did not mimic FSH activity this indicated that coexistence of estrogen/oocytes increases FSH activity at a site upstream of adenylate cyclase in granulosa cells. We therefore sought a possible involvement of the autoregulatory molecules for FSH receptor, G protein-coupled receptor kinases (GRKs) and beta-arrestins in enhancing FSH activity in response to the estrogen/oocyte co-treatment in granulosa cells. Among the seven known GRK and two beta-arrestin molecules, we found that estrogens with oocytes suppressed FSH-induced GRK-6 mRNA expression. Consistent with this finding, transfecting granulosa cells with small interfering RNA of GRK-6 significantly increased FSH induction of aromatase mRNA, suggesting that endogenous GRK-6 plays an inhibitory role in FSH-induced aromatase mRNA expression. Consequently, these findings strongly suggest that GRK-6 is involved in the mechanism by which estrogen and oocytes synergistically augment FSH activity in granulosa cells. (c) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.04.002

Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling. Reviewed International journal

Yoshinori Matsumoto, Fumio Otsuka, Mariko Takano-Narazaki, Takayuki Katsuyama, Eri Nakamura, Naoko Tsukamoto, Kenichi Inagaki, Ken-Ei Sada, Hirofumi Makino

Steroids 78 ( 5 ) 513 - 20 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Imbalanced functions of osteoclasts and osteoblasts are involved in various types of bone damage including postmenopausal osteoporosis. In the present study, we investigated the cellular mechanism by which estrogen interacts in the process of osteoblastic differentiation regulated by BMP-4 using mouse MC3T3-E1 cells that express estrogen receptors (ER) and BMP-4. Estradiol enhanced BMP-4-induced Runx2, osterix, ALP and osteocalcin expression in MC3T3-E1 cells. BMP-4-induced mineralization shown by Alizarin red staining was also facilitated by estrogen treatment. It was revealed that estrogen upregulated BMP-4-induced Smad1/5/8 phosphorylation, BRE-Luc activity and Id-1 mRNA expression. The expression of BMPRII was increased by estrogen in MC3T3-E1 cells, and inhibition of BMPRII or ALK-2/3 signaling impaired the effect of estrogen on BMP-4 signaling. Of note, the enhanced expression of osterix, ALP and osteocalcin mRNAs induced by BMP-4 and estrogen was reversed in the presence of an ER antagonist. Given that membrane-impermeable estrogen also upregulated BMP-4-induced expression of osteoblastic markers and Id-1 mRNA, non-genomic ER activity is involved in the mechanism by which estrogen enhances BMP-4-induced osteoblast differentiation in MC3T3-E1 cells. On the other hand, the expression of ERα and endogenous BMP-4 was suppressed by BMP-4 treatment regardless of the presence of estrogen, implying the presence of a negative feedback loop for osteoblast differentiation. Thus, estrogen is functionally involved in the process of osteoblast differentiation regulated by BMP-4 through upregulating BMP sensitivity of MC3T3-E1 cells.

DOI： 10.1016/j.steroids.2013.02.011

中枢性尿崩症で発症したリンパ球性汎下垂体炎の1例 Reviewed

竹本玲加、大塚文男、森下美智子、森本尚孝、寺田洋明、斉藤信幸、正岡哲也、宮谷克也、田中健大

三豊総合病院雑誌 34 59 - 63 2013.4

左眼瞼下垂を契機に診断された若年胃癌のトルコ鞍部転移の一例 Reviewed

稲垣兼一、当真貴志雄、中村絵里、越智可奈子、塚本尚子、三好智子、三村由香里、小倉俊郎、大塚文男、槇野博史

ACTH Related Peptides 24 56 - 58 2013.3

Involvement of bone morphogenetic protein activity in somatostatin actions on ovarian steroidogenesis. Reviewed International journal

Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Kanako Ogura-Ochi, Tomoko Miyoshi, Kishio Toma, Masaya Takeda, Hirofumi Makino

The Journal of steroid biochemistry and molecular biology 134 67 - 74 2013.3

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Somatostatin is expressed in the hypothalamus, pancreas and gastrointestinal tracts and it inhibits the secretion of various hormones in vivo. In the rodent ovary, somatostatin receptor (SSTR) subtypes 2 and 5 are expressed in granulosa cells and oocytes. Somatostatin analogs have been clinically used for treatment of endocrine tumors. For this purpose, relatively high-dose or long-term treatments of somatostatin analogs are necessary; however, the direct and continuous impact of somatostatin analogs on gonadal functions has yet to be elucidated. In the present study, we investigated the effects of somatostatin analogs (octreotide and pasireotide) on ovarian steroidogenesis by rat primary granulosa cell culture. The expression levels of SSTR2 and SSTR5 in granulosa cells were upregulated by FSH treatment. Treatment with somatostatin analogs decreased FSH-induced estradiol production with reduction in aromatase mRNA expression, while the treatment also suppressed FSH-induced progesterone production with reduction of mRNAs levels of StAR, P450scc and 3 beta HSD2 in granulosa cells. This trend was also observed in a granulosa/oocyte co-culture condition. The effect of pasireotide was more potent than that of octreotide. FSH-induced synthesis of steroids and cAMP was also suppressed by somatostatin analog treatment. Notably, pretreatment with a BMP-binding protein, noggin reversed the suppressive effects of somatostatin analogs on progesterone and cAMP production, suggesting that the endogenous BMP system is functionally involved in the SSTR effects in granulosa cells. Treatment with BMP-2, -4, -6 and -7 decreased the mRNA expression of inhibitory Smads6 and 7, leading to enhancement of BMP actions detected by Id-1 transcription in granulosa cells. Collectively, the results revealed that SSTR activation modulates ovarian steroidogenesis by upregulating endogenous BMP activity in growing follicles. (c) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2012.10.018

Rapid Progression of Graves' Ophthalmopathy Despite the Administration of Thiamazole

Takayuki Katsuyama, Masaya Takeda, Fumio Otsuka, Kishio Toma, Kenichi Inagaki, Ken-Ei Sada, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Internal Medicine 52 ( 20 ) 2317 - 2320 2013

Is wet swab superior to dry swab as an intranasal screening test? Reviewed International journal

Hideharu Hagiya, Mitsunobu Mio, Tomoko Murase, Keiko Egawa, Yumi Kokumai, Taeko Uchida, Naoki Morimoto, Fumio Otsuka, Sumiko Shiota

Journal of intensive care 1 ( 1 ) 10 - 10 2013

Language：English Publishing type：Research paper (scientific journal)

Methicillin-resistant Staphylococcus aureus is still a great concern, and recognition of the carrier is essential for appropriate infection control in intensive care units. The utility of wet swab compared to dry swab as an intranasal screening test has not been well assessed yet. A comparative study of the wet and dry swab in its ability to detect the organism was performed against critically ill patients, and it was found that there were no statistically significant differences between the two different methods. The wet swab did not show increased sensitivity compared to dry one.

DOI： 10.1186/2052-0492-1-10

Group A streptococcal meningitis in a patient with palmoplantar pustulosis. Reviewed

Hideharu Hagiya, Fumio Otsuka

Internal medicine (Tokyo, Japan) 52 ( 23 ) 2675 - 8 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

A 64-year-old man with a 10-year history of palmoplantar pustulosis, a recent history of cranial surgery and a persistent upper airway infection presented with a high fever and deep coma. The patient was diagnosed with Group A Streptococcal meningitis and promptly treated with antibiotics. Although his general condition recovered well, sensorineural hearing loss and facial palsy remained. Group A Streptococcal meningitis is a rare condition, and its typical clinical picture and epidemiological features remain poorly understood. Physicians need to be more aware of this infection, which is extremely rare but frequently causes various complications and yields a high mortality.

DOI： 10.2169/internalmedicine.52.0499

Disseminated gonococcal infection in an elderly Japanese man. Reviewed

Hideharu Hagiya, Nobuhiko Onishi, Hirotaka Ebara, Yoshihisa Hanayama, Susumu Kokeguchi, Motoko Nose, Nobuchika Kusano, Fumio Otsuka

Internal medicine (Tokyo, Japan) 52 ( 23 ) 2669 - 73 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

We herein present the case of a 69-year-old Japanese man who had unprotected sexual contact with a local commercial sex worker in an East Asian country and was diagnosed as having disseminated gonococcal infection (DGI). The organism was confirmed to be Neisseria gonorrhoeae based on 16S rRNA sequencing and positive results for the cppB gene. This case indicates that a diagnosis of DGI should also be considered in elderly individuals. DGI potentially causes many complications, and the pathogen has recently been reported to be resistant to various antibiotics. Physicians must therefore pay more attention to the possible occurrence of DGI in various clinical settings.

DOI： 10.2169/internalmedicine.52.1033

Ineffectiveness of daptomycin in the treatment of septic pulmonary emboli and persistent bacteremia caused by methicillin-resistant Staphylococcus aureus. Reviewed

Hideharu Hagiya, Shingo Hagioka, Fumio Otsuka

Internal medicine (Tokyo, Japan) 52 ( 22 ) 2577 - 82 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

A 73-year-old man with long-term food deprivation and total parenteral nutrition was diagnosed with septic pulmonary emboli (SPE) and a persistent bacteremia caused by central line-associated blood stream methicillin-resistant Staphylococcus aureus (MRSA) infection. Although daptomycin (DAP) failed to treat the persistent bacteremia, linezolid successfully controlled it. DAP is inactivated by lung surfactant, and therefore, it should not be administered for lower respiratory infections. However, SPE caused by MRSA has been reported to be treatable with DAP since it is an infection of the lung parenchyma. We herein report the lack of effect of daptomycin in SPE treatment.

DOI： 10.2169/internalmedicine.52.0023

A comprehensive analysis of 174 febrile patients admitted to Okayama University Hospital. Reviewed

Hiromasa Ryuko, Fumio Otsuka

Acta medica Okayama 67 ( 4 ) 227 - 37 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Primary care physicians often encounter patients with fever of unknown origin and without apparent causes. Recent advances in laboratory medicine have facilitated diagnostic procedures;however, it is still difficult to determine the critical febrile factor at an early stage. We reviewed the medical records of 174 patients who were admitted due to a chief complaint of fever (>37.5℃) to our hospital during the period from 2004 to 2010. The patients were categorized into patients with infection, inflammation, neoplasm and drug-induced fever. Based on the analysis done by category, it was revealed that the patient's age, body temperature and duration of fever were closely related to the final diagnosis. Serum CRP levels were significantly low in the nonbacterial infection group, while serum levels of sIL-2R were high in neoplasm and drug-induced cases. CRP level on admission was weakly but significantly correlated with body temperature, while duration of fever was inversely related to body temperature. The effectiveness of PET-CT and tissue biopsy for diagnosis was considerably high, particularly in the categories of neoplasm and nonspecific inflammation, respectively, though the effectiveness of bacterial culture was low. Thus, a careful review of physical and laboratory information including body temperature, CRP level, duration of fever, gender difference and history of medication is indispensable for diagnosis. Stepwise categorization and disease classification by comprehensive and systemic checkup are very helpful for determining the causes of fever.

Multifunctional bone morphogenetic protein system in endocrinology.

Fumio Otsuka

Acta medica Okayama 67 ( 2 ) 75 - 86 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

New biological activities of bone morphogenetic proteins (BMPs) in the endocrine system have recently been revealed. The BMP system is composed of approximately 30 ligands and preferential combinations of type I and type II receptors. The BMP system not only induces bone formation but also plays unique tissue-specific roles in various organs. For instance, the ovarian BMP system is a physiological inhibitor of luteinization in growing ovarian follicles. In the ovary, the expression of oocyte-derived BMP-15 is critical for female reproduction. In the pituitary, BMP-4 is a key player for initial development of the anterior pituitary, while it is also functionally involved in some differentiated pituitary tumors, including prolactinoma and Cushing's disease. In the adrenal glands, BMP-6 and BMP-4 modulate aldosterone and catecholamine production, respectively, which contributes to a functional interaction between the cortex and medulla. In the present review, recent advances in BMP biology in the field of endocrinology are described and the possibility for clinical application of BMP activity is discussed.

An in vivo role of bone morphogenetic protein-6 in aldosterone production by rat adrenal gland. Reviewed International journal

Yoshinori Matsumoto, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Mariko Takano-Narazaki, Tomoko Miyoshi, Eri Nakamura, Kanako Ogura-Ochi, Masaya Takeda, Hirofumi Makino

The Journal of steroid biochemistry and molecular biology 132 ( 1-2 ) 8 - 14 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. We previously reported the presence of a functional BMP system including BMP-6 in human adrenocortical cells. BMP-6 contributes to Ang II-induced aldosterone production by activating Smad signaling, in which endogenous BMP-6 action is negatively controlled by Ang II in vitro. In the present study, we examined the in vivo role of BMP-6 in regulation of aldosterone by neutralizing endogenous BMP-6 in rats treated with immunization against BMP-6. Three-week-old male rats were actively immunized with rat mature BMP-6 antigen conjugated with keyhole limpet hemocyanin (KLH). The immunization treatment had no effect on bilateral adrenal weight or its ratio to body weight. Urinary aldosterone excretion was time-dependently increased during the 8-week observation period in the control group. Of note, the level of urinary aldosterone excretion in BMP-6-KLH-immunized rats was significantly reduced compared to that in the control group, suggesting that endogenous BMP-6 contributes to the induction of aldosterone production in vivo. Moreover, the level of urinary aldosterone/creatinine after 8-week treatment was significantly lowered by treatment with BMP-6-KLH. In contrast, with chronic Ang II treatment, urinary aldosterone and creatinine-corrected values at 8 weeks were not significantly different between the two groups, suggesting that the effects of BMP-6-KLH were impaired under the condition of chronic treatment with Ang II. The mRNA levels of Cyp1162, but not those of Star, P450scc and 3 beta hsd2, were significantly decreased in adrenal tissues isolated from BMP-6-KLH-immunized rats after 8-week treatment. Furthermore, the ratio of plasma aldosterone level to corticosterone was significantly decreased by immunization with BMP-6-KLH. Collectively, the results indicate that endogenous BMP-6 is functionally linked to aldosterone synthesis by the zona glomerulosa in the adrenal cortex in vivo. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2012.04.004

Evaluation of weekly-reduction regimen of glucocorticoids in combination with cyclophosphamide for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Japanese patients. Reviewed International journal

Yoshinori Matsumoto, Ken-Ei Sada, Fumio Otsuka, Mariko Takano, Noriko Toyota, Koichi Sugiyama, Hiroshi Wakabayashi, Tomoko Kawabata, Hirofumi Makino

Rheumatology international 32 ( 10 ) 2999 - 3005 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER HEIDELBERG

The current therapeutic regimen recommended by the European League against Rheumatism (EULAR) for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is continuation of initially administered doses of glucocorticoids (GCs) in combination with cyclophosphamide (CYC) for 1 month followed by gradual tapering. Considering the adverse effects of GCs, another tapering regimen of GCs with CYC, which was characterized by tapering GCs weekly, was reported by the British Society of Rheumatology (weekly-reduction regimen). The aim of the present study is to evaluate the safety and efficacy of this weekly-reduction regimen for Japanese AAV patients in comparison with the monthly-reduction regimen recommended by the EULAR. We retrospectively reviewed medical records of adult patients newly diagnosed with AAV during the period from April 2000 to December 2010. The outcome measures were rates of remission, relapse, infection, and GC-induced diabetes mellitus during the first 12 months. Clinical data in the two groups and categorial variables with a possible relation to the outcomes were compared by using the t test and chi-square test, respectively. Twenty-four patients were enrolled in our study. All of the patients achieved remission, and the rates of relapse during the first 12 months were not statistically different between the two groups (P = 0.16). Patients treated with the weekly-reduction regimen were less liable to have infection (P = 0.03) and impaired glucose tolerance (P = 0.017), compared with those treated with the monthly-reduction regimen. A therapeutic strategy using the weekly-reduction regimen of GCs would be effective and would have fewer side effects than the monthly-reduction regimen.

DOI： 10.1007/s00296-011-2136-z

Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. International journal

Kazufumi Nakamura, Satoshi Akagi, Aiko Ogawa, Kengo F Kusano, Hiromi Matsubara, Daiji Miura, Soichiro Fuke, Nobuhiro Nishii, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Aya Miura, Chikao Yutani, Tohru Ohe, Hiroshi Ito

International journal of cardiology 159 ( 2 ) 100 - 6 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

BACKGROUND: Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH. METHODS: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. RESULTS: Treatment with imatinib (0.1 to 10 μg/mL) significantly inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1 μg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15 min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1 μmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs. CONCLUSION: Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.

DOI： 10.1016/j.ijcard.2011.02.024

Regulatory role of kit ligand-c-kit interaction and oocyte factors in steroidogenesis by rat granulosa cells. Reviewed International journal

Tomoko Miyoshi, Fumio Otsuka, Eri Nakamura, Kenichi Inagaki, Kanako Ogura-Ochi, Naoko Tsukamoto, Masaya Takeda, Hirofumi Makino

Molecular and cellular endocrinology 358 ( 1 ) 18 - 26 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Although kit ligand (KL)-c-kit interaction is known to be critical for oogenesis and folliculogenesis, its role in ovarian steroidogenesis has yet to be elucidated. We studied the impact of KL-c-kit interaction in regulation of steroidogenesis using rat oocyte/granulosa cell co-culture. In the presence of oocytes, soluble KL suppressed FSH-induced estradiol production and aromatase mRNA expression without affecting FSH-induced progesterone production. The KL effect on steroidogenesis was interrupted by an anti-c-kit neutralizing antibody, suggesting that KL-c-kit interaction is involved in suppression of estrogen by granulosa cells through oocyte c-kit action. The cAMP-PKA pathway activity was not directly involved in the estrogen regulation by KL-c-kit action. It was of note that KL treatment increased the expression levels of oocyte-derived FGF-8, GDF-9 and BMP-6, while it reduced the expression levels of oocyte-derived BMP-15 in the oocyte-granulosa cell co-culture. Given the findings that FGF-8, but not GDF-9, BMP-6 or -15, suppressed FSH-induced estrogen production by granulosa cells, oocyte-derived FGF-8 is linked to suppression of FSH-induced estrogen production through the KL-c-kit interaction. Furthermore, the suppression of FSH-induced estrogen production by KL in the co-culture was reversed by a FGF receptor kinase inhibitor and the effect of the inhibitor was enhanced in combination with extracellular-domain protein of BMPRII, which interferes with BMP-15 and GDF-9 activities. Thus, the actions of endogenous oocyte factors including FGF-8 and BMP-15/GDF-9 were involved in the KL activity that inhibited FSH-induced estradiol production. Collectively, the results indicate that KL-c-kit interaction plays a role in estrogenic regulation through oocyte-granulosa cell communication. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2012.02.011

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