Role of Pin1 in the development of pulmonary hypertension and therapeutic application

• Project/Area Number: 16H05220
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: University of Tsukuba
• Principal Investigator: SAKAI Satoshi 筑波大学, 医学医療系, 講師 (30282362)
• Co-Investigator(Kenkyū-buntansha): 内田 隆史 東北大学, 農学研究科, 教授 (80312239) ; 柳川 徹 筑波大学, 医学医療系, 教授 (10312852) ; 正田 純一 筑波大学, 医学医療系, 教授 (90241827)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2018: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2016: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 肺高血圧症 / プロリン異性化酵素 / 肺動脈血管内皮細胞 / 内皮型一酸化窒素合成酵素 / Pin1 / eNOS / 肺動脈血管平滑筋細胞 / 血管平滑筋細胞 / 肺高血圧 / Pin1阻害薬 / 肺動脈血管平滑筋 / 増殖 / リン酸化

Outline of Final Research Achievements

We investigated the pathophysiological roles of peptidyl prolyl isomerase 1 (Pin1) in the development of pulmonary hypertension (PH). We generated hypoxia-induced PH model in Pin1-knockout mice (KO). Although wild type mice developed PH by hypoxia, KO did not develop. We hypothesized that Pin1 contributes to the injury of pulmonary arterial endothelial cell (PAEC); we performed in vitro experiments. Phosphorylated eNOS molecule was significantly increased by knockdown of Pin1; however, it did not differ by overexpression of Pin1. Apoptosis of PAEC was significantly suppressed by Pin1 knockdown; however, it was augmented by Pin1 overexpression. These findings suggests that Pin1 plays a role in exaggerating PH, partly via endothelial cell dysfunction in pulmonary arteries.

Academic Significance and Societal Importance of the Research Achievements

難治性疾患である肺動脈性肺高血圧症の病態をPin1というユニークな分子を通して解明しようとする研究であり、得られた結果は国内外を通しても初めてのものである。Pin1は肺動脈血管内皮細胞の内皮機能抑制と細胞死促進を介して肺高血圧を促進していることが明らかになった。肺動脈性肺高血圧症の治療効果は限定的であることから、Pin1抑制が新たな治療法として今後追加される可能性を提示できたものと考えられる。

Research Products

• [Journal Article] Endothelin and the heart in health and diseases (2019)
  • Author(s): Miyauchi Takashi、Sakai Satoshi
  • Journal Title: Peptides Volume: 111 Pages: 77-88
  • DOI: 10.1016/j.peptides.2018.10.002
  • Peer Reviewed / Open Access
• [Journal Article] Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization (2018)
  • Author(s): Kimura Taizo、Tajiri Kazuko、Sato Akira、Sakai Satoshi、Wang Zheng、Yoshida Toshimichi、Uede Toshimitsu、Hiroe Michiaki、Aonuma Kazutaka、Ieda Masaki、Imanaka-Yoshida Kyoko
  • Journal Title: Cardiovascular Research Volume: 115 Issue: 3 Pages: 614-624
  • DOI: 10.1093/cvr/cvy244
  • Peer Reviewed
• [Journal Article] The glucagon-like peptide-1 receptor antagonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ETB receptor expression. (2018)
  • Author(s): Honda J, Kimura T, Sakai S, Maruyama H, Tajiri K, Murakoshi N, Homma S, Miyauchi T, Aonuma K
  • Journal Title: Physiological Research Volume: 67
  • Peer Reviewed / Open Access
• [Journal Article] Effects of resistance training on arterial compliance and plasma endothelin-1 levels in healthy men. (2018)
  • Author(s): Tagawa K, Ra SG, Kumagai H, Yoshikawa Y, Takekoshi K, Sakai S, Miyauchi T, Maeda S
  • Journal Title: Physiological Research Volume: 67
  • Peer Reviewed / Open Access
• [Journal Article] Exercise habituation is effective for improvement of periodontal disease status: a prospective intervention study. (2018)
  • Author(s): Omori S, Uchida F, Oh S, So R, Tsujimoto T, Yanagawa T, Sakai S, Shoda J, Tanaka K, Bukawa H.
  • Journal Title: Ther Clin Risk Manag Volume: 14 Pages: 565-574
  • DOI: 10.2147/tcrm.s153397
  • NAID: 120007134309
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP-2 expression. (2018)
  • Author(s): Nagai H, Hasegawa S, Uchida F, Terabe T, Ishibashi Kanno N, Kato K, Yamagata K, Sakai S, Kawashiri S, Sato H, Yanagawa T, Bukawa H.
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 841-850
  • DOI: 10.3892/ijo.2018.4260
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 is required sperm production by promoting mitosis progression of spermatogonial stem cells. (2018)
  • Author(s): Kurita-Suzuki A, Kamo Y, Uchida C, Tanemura K, Hara K, Uchida T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 497 Issue: 1 Pages: 388-393
  • DOI: 10.1016/j.bbrc.2018.02.090
  • Peer Reviewed / Open Access
• [Journal Article] Food polyphenols targeting peptidyl prolyl cis/trans isomerase Pin1. (2018)
  • Author(s): Hidaka M, Kosaka K, Tsushima S, Uchida C, Takahashi K, Takahashi N, Tsubuki M, Hara Y, Uchida T
  • Journal Title: Biochem Biophys Res Commun Volume: 499 Issue: 3 Pages: 681-687
  • DOI: 10.1016/j.bbrc.2018.03.212
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of both <i>p62</i> and <i>Nrf2</i> spontaneously results in the development of nonalcoholic steatohepatitis (2018)
  • Author(s): AKIYAMA Kentaro、WARABI Eiji、OKADA Kosuke、YANAGAWA Toru、ISHII Tetsuro、KOSE Katsumi、TOKUSHIGE Katsutoshi、ISHIGE Kazunori、MIZOKAMI Yuji、YAMAGATA Kenji、ONIZAWA Kojiro、ARIIZUMI Shun-ichi、YAMAMOTO Masakazu、SHODA Junichi
  • Journal Title: Experimental Animals Volume: 67 Issue: 2 Pages: 201-218
  • DOI: 10.1538/expanim.17-0112
  • NAID: 130006733609
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination (2018)
  • Author(s): Ogawa M, Matsuda R, Takada N, Tomokiyo M, Yamamoto S, Shizukusihi S, Yamaji T, Yoshikawa Y, Yoshida M, Tanida I, Koike M, Murai M, Morita H, Takeyama H, Ryo A, Guan JL, Yamamoto M, Inoue JI, Yanagawa T, Fukuda M, Kawabe H, Ohnishi M
  • Journal Title: Cellular Microbiology Volume: e12846 Issue: 8
  • DOI: 10.1111/cmi.12846
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy and Safety of an Orally Administered Selective Prostacyclin Receptor Agonist, Selexipag, in Japanese Patients With Pulmonary Arterial Hypertension (2017)
  • Author(s): Tanabe N, Ikeda S, Tahara N, Fukuda K, Hatano M, Ito H, Nakayama T, Anzai T, Hashimoto A, Inoue T, Kajinami K, Kihara Y, Kinoshita H, Kuwahara K, Murohara T, Okazaki O, Sakai S, Satoh T, Takeda Y, Takeishi Y, Taniguchi M, Watanabe H, Yamamoto T, Yamauchi-Takihara K, Yoshioka K, Sasayama S.
  • Journal Title: Circulation Journal Volume: 81 Issue: 9 Pages: 1360-1367
  • DOI: 10.1253/circj.CJ-16-1348
  • NAID: 130006003900
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The effectiveness of upfront pulmonary vasodilators combination therapy in addition to corticosteroids for pulmonary arterial hypertension associated with systemic lupus erythematosus: two successful cases utilising both corticosteroids and an upfront combination of vasodilators (2017)
  • Author(s): Abe S、Tsuboi H、Toko H、Honda F、Ohyama A、Takahashi H、Yokosawa M、Asashima H、Hagiwara S、Hirota T、Kondo Y、Matsumoto I、Sakai S、Aonuma K、Sumida T
  • Journal Title: Modern Rheumatol Case Reports Volume: 1 Issue: 2 Pages: 73-78
  • DOI: 10.1080/24725625.2016.1277457
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis (2017)
  • Author(s): Xu Tao、Zhang Honglai、Park Sung-Soo、Venneti Sriram、Kuick Rork、Ha Kimberly、Michael Lowell Evan、Santi Mariarita、Uchida Chiyoko、Uchida Takafumi、Srinivasan Ashok、Olson James M.、Dlugosz Andrzej、Camelo-Piragua Sandra、Rual Jean-Fransois
  • Journal Title: Neoplasia Volume: 19 Issue: 3 Pages: 216-225
  • DOI: 10.1016/j.neo.2017.01.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 promotes proplatelet formation of megakaryocytes via tau (2017)
  • Author(s): Shimizu Taiki、Uchida Chiyoko、Shimizu Ritsuko、Motohashi Hozumi、Uchida Takafumi
  • Journal Title: Biochem Biophys Res Commun Volume: 493 Issue: 2 Pages: 946-951
  • DOI: 10.1016/j.bbrc.2017.09.115
  • Peer Reviewed
• [Journal Article] Peptidyl-Prolyl Isomerase 1 Regulates Ca(2+) Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na(2+)/Ca(2+) Exchanger 1 Protein Levels and Function. (2017)
  • Author(s): Sacchi V, Wang BJ, Kubli D, Martinez AS, Jin JK, Alvarez R Jr, Hariharan N, Glembotski C, Uchida T, Malter JS, Yang Y, Gross P, Zhang C, Houser S, Rota M, Sussman MA
  • Journal Title: J Am Heart Assoc Volume: 493 Issue: 10
  • DOI: 10.1161/jaha.117.006837
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis. (2017)
  • Author(s): Komine S, Akiyama K, Warabi E, Oh S, Kuga K, Ishige K, Togashi S, Yanagawa T, Shoda J
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 11977-11977
  • DOI: 10.1038/s41598-017-12358-8
  • NAID: 120007134775
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Skeletal muscle mass to visceral fat area ratio is an important determinant affecting hepatic conditions of non-alcoholic fatty liver disease (2017)
  • Author(s): Shida Takashi、Akiyama Kentaro、Oh Sechang、Sawai Akemi、Isobe Tomonori、Okamoto Yoshikazu、Ishige Kazunori、Mizokami Yuji、Yamagata Kenji、Onizawa Kojiro、Tanaka Hironori、Iijima Hiroko、Shoda Junichi
  • Journal Title: J Gastroenterol Volume: 53 Issue: 4 Pages: 535-547
  • DOI: 10.1007/s00535-017-1377-3
  • Peer Reviewed / Open Access
• [Journal Article] Wisteria floribunda Agglutinin-Sialylated Mucin Core Polypeptide 1 is a Sensitive Biomarker for Biliary Tract Carcinoma and Intrahepatic Cholangiocarcinoma: A Multicenter Study. (2016)
  • Author(s): Shoda J, Matsuda A, Shida T, Yamamoto M, Nagino M, Tsuyuguchi T, Yasaka T, Tazuma S, Uchiyama K, Unno M, Ohkohchi N, Nakanuma Y, Kuno A, Narimatsu H.
  • Journal Title: J Gastroenterol Volume: 52 Issue: 2 Pages: 218-228
  • DOI: 10.1007/s00535-016-1230-0
  • Peer Reviewed / Open Access
• [Journal Article] Antagonists to endothelin receptor type B promone apoptosis in human pulmonary arterial smooth muscle cells. (2016)
  • Author(s): Sakai S, Maruyama H, Kimura T, Tajiri K, Honda J, Homma S, Aonuma K, Miyauchi T
  • Journal Title: Life Sci Volume: In print Pages: 116-120
  • DOI: 10.1016/j.lfs.2016.03.044
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bosentan reverses the hypoxia-induced downregulation of the bone morphogenetic protein signaling in pulmonary artery smooth muscle cells (2016)
  • Author(s): Maruyama, H. Dewachter, C. Sakai, S. Belhaj, A. Rondelet, B. Remmelink, M. Vachiery, J. L. Naeije, R. Dewachter, L.
  • Journal Title: Life Sci Volume: 159 Pages: 111-115
  • DOI: 10.1016/j.lfs.2016.05.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p62 modulates the intrinsic signaling of UVB-induced apoptosis. (2016)
  • Author(s): Ito S, Kimura S, Warabi E, Kawachi Y, Yamatoji M, Uchida F, Ishibashi-Kanno N, Yamagata K, Hasegawa S, Shoda J, Tabuchi K, Sakai S, Bukawa H, Sekido M, Yanagawa T.
  • Journal Title: Journal of Dermatological Science Volume: 83 Issue: 3 Pages: 226-233
  • DOI: 10.1016/j.jdermsci.2016.05.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-155-5p is associated with oral squamous cell carcinoma metastasis and poor prognosis (2016)
  • Author(s): Osamu Baba,Shogo Hasegawa,Hiroki Nagai,Fumihiko Uchida,Masanobu Yamatoji,Naomi I. Kanno,Kenji Yamagata,Satoshi Sakai,Toru Yanagawa,Hiroki Bukawa
  • Journal Title: Journal of Oral Pathology & Medicine Volume: 45 Issue: 4 Pages: 248-255
  • DOI: 10.1111/jop.12351
  • NAID: 120007135548
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension (2016)
  • Author(s): Tahara N, Dobashi H, Fukuda K, Funauchi M, Hatano M, Ikeda S, Joho S, Kihara Y, Kimura T, Kondo T, Matsushita M, Minamino T, Nakanishi N, Ozaki Y, Saji T, Sakai S, Tanabe N, Watanabe H, Yamada H, Yoshioka K, Sasayama S
  • Journal Title: Circulation Journal Volume: 80 Issue: 6 Pages: 1478-1483
  • DOI: 10.1253/circj.CJ-15-1305
  • NAID: 130005153579
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-intensity aerobic exercise improves both hepatic fat content and stiffness in sedentary obese men with non-alcoholic fatty liver disease: A randomized controlled study. (2016)
  • Author(s): Oh S, So R, Shida T, Matsuo T, Kim B, Akiyama K, Isobe T, Okamoto Y, Tanaka K, Shoda J.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 43029-43029
  • DOI: 10.1038/srep43029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Regulates Doxorubicin- Inducible P-glycoprotein Level by Reducing Foxo3 Stability. (2016)
  • Author(s): Shimizu T, Bamba Y, Kawabe Y , Fukuda T, Fujimori F, Takahashi K, Uchida C, and Uchida T
  • Journal Title: Biochemical Biophysical Research Communications Volume: 471 Issue: 2 Pages: 328-333
  • DOI: 10.1016/j.bbrc.2016.02.014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the γ subunit (2015)
  • Author(s): Nakatsu Y, Iwashita M, Sakoda H, Ono H, Nagata K, Matsunaga Y, Fukushima T, Fujishiro M, Kushiyama A, Kamata H, Takahashi S, Katagiri H, Honda H, Kiyonari H, Uchida T, Asano T
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 24255-24266
  • DOI: 10.1074/jbc.m115.658559
  • Peer Reviewed / Open Access
• [Presentation] Peptidyl prolyl isomerase (Pin1) contributes to the development of pulmonary hypertension partly via pulmonary vascular endothelial cell dysfunction (2019)
  • Author(s): Sakai S, Maruyama H, Honda J, Ieda M
  • Organizer: 第83回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Metabolic analysis in the lung of mice with hypoxia-induced pulmonary hypertension (2019)
  • Author(s): Sakai S, Maruyama H, Honda J, Ieda M
  • Organizer: 第83回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] The glucagon-like pepetide-1 receptor agonist liraglutide ameriolates hypoxia-induced pulmonary hypertension in mice partly via recovery of ETB receptor expression. (2018)
  • Author(s): Honda J, Kimura T, Sakai S, Maruyama H, Homma S, Miyauchi T, Aonuma K
  • Organizer: Congress of the European-Society-of-Cardiology (ESC) 2018
  • Int'l Joint Research
• [Presentation] Active selexipag-metabolite MRE-269 induces DUSP1 and inhibits PASMC proliferation. (2018)
  • Author(s): Maruyama H, Sakai S, Aonuma K
  • Organizer: Congress of the European-Society-of-Cardiology (ESC) 2018
  • Int'l Joint Research
• [Presentation] MAIR-II deficiency prevents excessive inflammation and fibrosis protecting against cardiac dysfunction post-myocardial infarction. (2018)
  • Author(s): Yonebayashi S, Tajiri K, Murakoshi N, Yamagami F, Okabe Y, Feng D, Qin R, Sakai S, Shibuya A, Aonuma K, Ieda M
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] Blockade of endothelin receptor type B promotes apoptosis in human pulmonary arterial smooth muscle cells (2018)
  • Author(s): Sakai S, Maruyama H, KImura T, Honda J, Otsu K, Homma S, Miyauchi T, Aonuma K
  • Organizer: Sixth World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] Altered BMP signaling by endothelin-1 to accelerate proliferation of smooth muscle cells (2018)
  • Author(s): Maruyama H, Sakai S, Aonuma K
  • Organizer: Sixth World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] The decrease of S-wave amplitude in V5 lead of electrocardiography positively reflects effectual treatment in patients with pulmonary hypertension (2017)
  • Author(s): Otsu K, Sakai S, Kimura T, Miyauchi T, Homma S, Aonuma K
  • Organizer: 第８１回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2017-03-17
• [Presentation] Glucagon-like peptide-1 receptor agonist liraglutide inhibits hypoxia-induced pulmonary hypertension in mice partly via recovery or ETB receptor expression (2017)
  • Author(s): Honda J, Kimura T, Sakai S, Maruyama H, Homma S, Miyauchi T, Aonuma K
  • Organizer: The 15th International Conference on Endothelin
  • Int'l Joint Research
• [Presentation] 肺動脈性肺高血圧症におけるPGI2系薬剤の位置づけ (2017)
  • Author(s): 酒井 俊
  • Organizer: 第65回日本心臓病学会学術集会
  • Invited
• [Presentation] BMP2 induces DUSP1 in pulmonary artery smooth muscle cells. (2017)
  • Author(s): Maruyama H, Sakai S, Aonuma K
  • Organizer: Congress of the European-Society-of-Cardiology (ESC) 2017
  • Int'l Joint Research
• [Presentation] Endothelin-1 modifies BMP signaling pathway to induce cyclin D1 in pulmonary smooth muscle cells. (2017)
  • Author(s): Maruyama H, Sakai S, Aonuma K
  • Organizer: Congress of the European-Society-of-Cardiology (ESC) 2017
  • Int'l Joint Research
• [Presentation] ヒト肺動脈血管平滑筋細胞に対するETB受容体遮断による影響 (2016)
  • Author(s): 酒井俊・丸山秀和・木村泰三・田尻和子・本田洵也・本間覚・青沼和隆・宮内卓
  • Organizer: 第20回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 東京コンベンションホール（東京都中央区）
  • Year and Date: 2016-12-16
• [Presentation] Hypoxia induces the down regulation of the BMP signaling in pulmonary artery smooth muscle cells through the endothelin system (2016)
  • Author(s): Maruyama H, Sakai S, Naeije R, Dewachter L, Aonuma K
  • Organizer: Congress of the European-Society-of-Cardiology (ESC) 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Lysil oxidase was increased by endothelin-1 and restored by PGI2 in pulmonary artery smooth muscle cells (2016)
  • Author(s): Maruyama H, Sakai S, Naeije R, Dewachter L, Aonuma K
  • Organizer: Congress of the European-Society-of-Cardiology (ESC) 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Pulmonary hypertension is ameliorated by glucagon-like peptide-1 receptor agonist partly via eNOS activation (2016)
  • Author(s): Sakai S, Kimura T, Honda J, Tajiri K, Homma S, Aonuma K, Miyauchi T
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications f Nitric Oxide
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research