Papers - Shimizu, Ryoko

Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor

Matsuo M., Hirota Y., Fukui Y., Fujita H., Saito-Fujita T., Kaku T., Gebril M., Hirata T., Akaeda S., Hiraoka T., Tanaka T., Haraguchi H., Saito-Kanatani M., Shimizu-Hirota R., Takeda N., Fujii T., Osuga Y.

Endocrinology (Endocrinology)  161 ( 2 )  2020.02

　View Summary

© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 μg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 μg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.

• Access to Document (DOI)

Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

Haraguchi H., Hirota Y., Saito-Fujita T., Tanaka T., Shimizu-Hirota R., Harada M., Akaeda S., Hiraoka T., Matsuo M., Matsumoto L., Hirata T., Koga K., Wada-Hiraike O., Fujii T., Osuga Y.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB journal : official publication of the Federation of American Societies for Experimental Biology)  33 ( 2 ) 2610 - 2620 2019.02

ISSN  08926638

　View Summary

Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 deficiency in ovarian granulosa cells [ Mdm2-loxP/ progesterone receptor ( Pgr)-Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells ( Mdm2-loxP/ p53-loxP/ Pgr-Cre mice) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 deletion in ovarian granulosa cells ( Mdm2-loxP/ anti-Mullerian hormone type 2 receptor-Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization. Mdm2-p53 pathway in cumulus granulosa cells transcriptionally controlled an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that the Mdm2-p53-SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.-Haraguchi, H., Hirota, Y., Saito-Fujita, T., Tanaka, T., Shimizu-Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada-Hiraike, O., Fujii, T., Osuga, Y. Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality.

• Access to Document (DOI)

Negative effect of fatty liver on visualization of pancreatic cystic lesions at screening transabdominal ultrasonography

Kashiwagi K., Seino T., Makino K., Shimizu-Hirota R., Takayama M., Yoshida T., Iwasaki E., Sugino Y., Inoue N., Iwao Y., Kanai T.

Journal of Evaluation in Clinical Practice (Journal of Evaluation in Clinical Practice)  26 ( 1 ) 256 - 261 2019

ISSN  13561294

　View Summary

© 2019 John Wiley & Sons, Ltd. Rationale, aims, and objectives: The aim of this observational study is to identify factors by which some pancreatic cystic lesions (PCLs) were undetectable at transabdominal ultrasonography (TAUS), using magnetic resonance imaging (MRI) as reference standard. Methods: The database for 781 consecutive subjects who underwent a health checkup including fat computed tomography and upper abdominal MRI as option was searched. The presence of fatty liver and fatty pancreas was diagnosed by TAUS, and atrophic pancreas was determined by reevaluating the image of the pancreas in the chest computed tomography for screening. Subjects with PCL detected and those undetected at TAUS were statistically compared in clinical characteristics. Results: The prevalence of PCL detected at MRI was 17.8% in the general population. Multivariate logistic regression analysis showed that fatty liver, body mass index, and the size of PCL were significantly associated with the factors influencing the visualization of PCL at TAUS (odds ratio [OR]: 0.337, 95% confidence interval [CI]: 0.154-0.734, P = 0.006; OR: 0.852, 95% CI: 0.737-0.985, P = 0.030; OR:1.120, 95% CI: 1.045-1.200, P =.001). Thirty-six PCLs (64.3%) in a total of 56 PCLs were undermeasured by TAUS. Additionally, nine (56%) out of 16 PCLs (≥ 15 mm) were undermeasured by 5 mm or more by TAUS, although a significantly higher detection rate was observed for PCLs (≥ 15 mm) in comparison with that for PCLs (< 15 mm) (80% vs 33.6%, P =.000). Conclusions: It should be noted that coexisting fatty liver may lower the detection of PCL, and its size may be underestimated by TAUS.

• Access to Document (DOI)

HIF2 alpha in the uterine stroma permits embryo invasion and luminal epithelium detachment

Matsumoto, Leona, Hirota, Yasushi, Saito-Fujita, Tomoko, Takeda, Norihiko, Tanaka, Tomoki, Hiraoka, Takehiro, Akaeda, Shun, Fujita, Hidetoshi, Shimizu-Hirota, Ryoko, Igaue, Shota, Matsuo, Mitsunori, Haraguchi, Hirofumi, Saito-Kanatani, Mayuko, Fujii, Tomoyuki, Osuga, Yutaka

JOURNAL OF CLINICAL INVESTIGATION (Journal of Clinical Investigation)  128 ( 7 ) 3186 - 3197 2018.07

Research paper (scientific journal),  ISSN  0021-9738

　View Summary

© 2018 American Society for Clinical Investigation. All rights reserved. Although it has been reported that hypoxia inducible factor 2 a (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P 4 ) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2a in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2a regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2a allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.

• Access to Document (DOI)

F4/80(+) Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus

Egashira, Mahiro, Hirota, Yasushi, Shimizu-Hirota, Ryoko, Saito-Fujita, Tomoko, Haraguchi, Hirofumi, Matsumoto, Leona, Matsuo, Mitsunori, Hiraoka, Takehiro, Tanaka, Tomoki, Akaeda, Shun, Takehisa, Chiaki, Saito-Kanatani, Mayuko, Maeda, Kei-ichiro, Fujii, Tomoyuki, Osuga, Yutaka

ENDOCRINOLOGY 158 ( 7 ) 2344 - 2353 2017.07

Research paper (scientific journal),  ISSN  0013-7227

• Access to Document (DOI)

Investigation of Metabolic Factors Associated with eGFR Decline Over 1 Year in a Japanese Population without CKD

Hayashi, Kaori, Takayama, Michiyo, Abe, Takayuki, Kanda, Takeshi, Hirose, Hiroshi, Shimizu-Hirota, Ryoko, Shiomi, Eisuke, Iwao, Yasushi, Itoh, Hiroshi

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 24 ( 8 ) 863 - 875 2017

Research paper (scientific journal),  ISSN  1340-3478

• Access to Document (DOI)

RELATIONSHIPS OF VISCERAL FAT AREA AND INSULIN RESISTANCE INDEX WITH BLOOD PRESSURE STATUS

Hirose, Hiroshi, Takayama, Michiyo, Shimizu-Hirota, Ryoko, Iwao, Yasushi, Kawabe, Hiroshi

JOURNAL OF HYPERTENSION 34   E393 - E393 2016.09

Research paper (scientific journal),  ISSN  0263-6352

Serum High-Molecular-Weight Adiponectin Levels Correlate with Various Metabolic Parameters in Special Health Checkup Programs

Hirose, Hiroshi, Azuma, Koichiro, Shimizu-Hirota, Ryoko, Taka-Yama, Michiyo, Iwao, Yasushi, Kawabe, Hiroshi

DIABETES 65   A626 - A627 2016.06

Research paper (scientific journal),  ISSN  0012-1797

Metabolic Factors in Addition to Aging and Current Smoking Are Independently Associated With the Prevalence of Colorectal Neoplasia in Japan: Analyses of Comprehensive Health Checkup Data

Inoue, Nagamu, Takayama, Michiyo, Makino, Kanako, Shiomi, Eisuke, Shimizu-Hirota, Ryoko, Yoshida, Toshifumi, Kashiwagi, Kazuhiro, Hirose, Hiroshi, Momoshima, Suketaka, Sugino, Yoshinori, Iwao, Yasushi

GASTROENTEROLOGY 150 ( 4 ) S767 - S768 2016.04

Research paper (scientific journal),  ISSN  0016-5085

Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture

Anzai Atsushi, Shimoda Masayuki, Endo Jin, Kohno Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Yamamoto Tsunehisa, Ito Kentaro, Yan Xiaoxiang, Shirakawa Kosuke, Shimizu-Hirota Ryoko, Yamada Yoshitake, Ueha Satoshi, Shinmura Ken, Okada Yasunori, Fukuda Keiichi, Sano Motoaki

Circulation Research 116 ( 4 ) 612 - 623 2015.02

ISSN  0009-7330

　View Summary

<p>Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.</p>

• Access to Document (DOI)

Neutrophil-derived matrix metalloproteinase 9 triggers acute aortic dissection

Kurihara Tomohiro, Shimizu-Hirota Ryoko, Shimoda Masayuki, Adachi Takeshi, Shimizu Hideyuki, Weiss Stephen J., Itoh Hiroshi, Hori Shingo, Aikawa Naoki, Okada Yasunori

Circulation 126 ( 25 ) 3070 - 3080 2012.12

ISSN  0009-7322

　View Summary

<p>BACKGROUND-: Acute aortic dissection (AAD) is a life-threatening vascular disease without effective pharmaceutical therapy. Matrix metalloproteinases (MMPs) are implicated in the development of chronic vascular diseases including aneurysm, but the key effectors and mechanism of action remain unknown. To define further the role of MMPs in AAD, we screened circulating MMPs in AAD patients, and then generated a novel mouse model for AAD to characterize the mechanism of action. METHODS AND RESULTS-: MMP9 and angiotensin II were elevated significantly in blood samples from AAD patients than in those from the patients with nonruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, β-aminopropionitrile monofumarate. AAD was developed successfully in the thoracic aorta by angiotensin II administration to β-aminopropionitrile monofumarate-treated wild-type mice, with an incidence of 20%, 80%, and 100% after 6, 12, and 24 hours, respectively. Neutrophil infiltrations were observed in the intima of the thoracic aorta, and the overexpression of MMP9 in the aorta was demonstrated by reverse transcription polymerase chain reaction, gelatin zymography, and immunohistochemistry. The incidence of AAD was reduced significantly by 40% following the administration of an MMP inhibitor and was almost blocked completely in MMP mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of anti-granulocyte- differentiation antigen-1 (anti-Gr-1) antibody also significantly decreased the incidence of AAD. CONCLUSIONS-: These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II. © 2012 American Heart Association, Inc.</p>

• Access to Document (DOI)

MT1-MMP regulates the PI3Kδ-Mi-2/NuRD-dependent control of macrophage immune function

Shimizu-Hirota Ryoko, Xiong Wanfen, Baxter B. Timothy, Kunkel Steven L., Maillard Ivan, Chen Xiao Wei, Sabeh Farideh, Liu Rui, Li Xiao Yan, Weiss Stephen J.

Genes and Development 26 ( 4 ) 395 - 413 2012.02

ISSN  0890-9369

　View Summary

<p>Macrophages play critical roles in events ranging from host defense to obesity and cancer, where they infiltrate affected tissues and orchestrate immune responses in tandem with the remodeling of the extracellular matrix (ECM). Despite the dual roles played by macrophages in inflammation, the functions of macrophage-derived proteinases are typically relegated to tissue-invasive or -degradative events. Here we report that the membrane-tethered matrix metalloenzyme MT1-MMP not only serves as an ECM-directed proteinase, but unexpectedly controls inflammatory gene responses wherein MT1-MMP ^-/- macrophages mount exaggerated chemokine and cytokine responses to immune stimuli both in vitro and in vivo. MT1-MMP modulates inflammatory responses in a protease-independent fashion in tandem with its trafficking to the nuclear compartment, where it triggers the expression and activation of a phosphoinositide 3-kinase d (PI3Kδ)/Akt/GSK3b signaling cascade. In turn, MT1-MMP-dependent PI3Kδ activation regulates the immunoregulatory Mi-2/NuRD nucleosome remodeling complex that is responsible for controlling macrophage immune response. These findings identify a novel role for nuclear MT1-MMP as a previously unsuspected transactivator of signaling networks central to macrophage immune responses. © 2012 by Cold Spring Harbor Laboratory Press.</p>

• Access to Document (DOI)

Hepatocyte-derived snail1 propagates liver fibrosis progression

Rowe R. Grant, Lin Yongshun, Shimizu-Hirota Ryoko, Hanada Shinichiro, Neilson Eric G., Greenson Joel K., Weiss Stephen J.

Molecular and Cellular Biology 31 ( 12 ) 2392 - 2403 2011.06

ISSN  0270-7306

　View Summary

<p>Chronic exposure of the liver to hepatotoxic agents initiates an aberrant wound healing response marked by proinflammatory, as well as fibrotic, changes, leading to compromised organ structure and function. In a variety of pathological states, correlative links have been established between tissue fibrosis and the expression of transcription factors associated with the induction of epithelial-mesenchymal cell transition (EMT) programs similar to those engaged during development. However, the role played by endogenously derived, EMT-associated transcription factors in fibrotic states in vivo remains undefined. Using a mouse model of acute liver fibrosis, we demonstrate that hepatocytes upregulate the expression of the zinc finger transcriptional repressor, Snail1, during tissue remodeling. Hepatocyte-specific ablation of Snail1 demonstrates that this transcription factor plays a key role in liver fibrosis progression in vivo by triggering the proximal genetic programs that control multiple aspects of fibrogenesis, ranging from growth factor expression and extracellular matrix biosynthesis to the ensuing chronic inflammatory responses that characterize this class of pathological disorders. © 2011, American Society for Microbiology. All Rights Reserved.</p>

• Access to Document (DOI)

Protease-dependent versus-independent cancer cell invasion programs

Sabeh Farideh, Shimizu-Hirota Ryoko, Weiss Stephen J.

Journal of Cell Biology 185 ( 1 ) 11 - 19 2009.04

ISSN  0021-9525

• Access to Document (DOI)

トランスジェニックマウスを用いた細胞外マトリックス糖蛋白バイグリカンの血管における機能の役割

'清水良子,篠村裕之,猿田享男'

血圧 12 ( 3 ) 351-356 2005.03

Research paper (scientific journal), Single Work

肝細胞増殖因子(HGF)によるプロテオグリカン発現調節機構の検討

小林絵美、篠村裕之、三船瑞夫、清水 良子、黒田真理、林松彦、猿田享男

血圧 11 ( 3 ) 241-247 2004.03

Research paper (scientific journal), Joint Work

Glomerular expression of biglycan and decorin and urinary levels of decorin in primary glomerular disease.

'Kuroda M, Sasamura H, Shimizu-Hirota R, Nakazato Y, Hayashi M, Saruta T'

Clinical Nephrology 61 ( 1 ) 7月16日 2004.01

Research paper (scientific journal), Joint Work, Accepted

'Functional characterization of podocan, a member of a new class in the small leucine-rich repeat protein family.'

'Shimizu-Hirota R , Sasamura H, Kuroda M, Kobayashi E, Saruta T'

FEBS Letters 563 ( 1月3日 ) 69-74 2004.01

Research paper (scientific journal), Single Work, Accepted

Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell proliferation and migration.

'Shimizu-Hirota R , Sasamura H, Kuroda M, Kobayashi E, Hayashi M, Saruta T'

Circulation Research 94 ( 8 ) 1067-1074 2004

Research paper (scientific journal), Single Work, Accepted

Hepatocyte growth factor regulates proteoglycan synthesis in intersitial fibroblasts.

'Kobayashi E, Sasamura H, Mifune M, Shimizu-Hirota R, Kuroda M, Hayashi M, Saruta T'

Kidney International 64 ( 4 ) 1179-1188 2003.10

Research paper (scientific journal), Joint Work, Accepted