Prostaglandin E2 receptor EP4 regulates fibrotic changes via TGF-beta in cardiac fibroblast cells

• Project/Area Number: 19K08563
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yokohama City University
• Principal Investigator: UMEMURA Masanari 横浜市立大学, 医学部, 講師 (50595353)
• Co-Investigator(Kenkyū-buntansha): 横山 詩子 東京医科大学, 医学部, 主任教授 (70404994)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 心臓線維芽細胞 / EP4 / TGF-β / 線維化 / CTGF / カルシウム / 心臓筋芽細胞 / 心臓線維化 / ドキソルビシン / Onco-cardiology / プロスタグランディン

Outline of Research at the Start

心臓における線維芽細胞は線維化への関与だけでなく、様々なサイトカインや成長
ホルモンを介して心筋細胞に直接作用し、細胞収縮や肥大、さらには細胞生存性を制御することが明らかになっている。プロスタグランディンE(PGE)受容体EP4欠損マウスではコントロールと比較し、アンジオテンシンⅡ負荷による心臓の線維化が著しく亢進していることを見出した。本研究では、EP4受容体が、TGF-βを介して心臓線維化の強力な新規調節分子として働いていることを証明し、心臓線維化への作用を解析する。最終目標は、EP4を制御することで、心臓の線維化の進行を抑制する初めてのEP4作動薬の開発への基盤となる知見を得ることである。

Outline of Final Research Achievements

The EP4 prostanoid receptor is one of the four receptor subtypes for Prostaglandin E2 (PGE2). It is known that EP4 is highly expressed in the heart and has protective effects against adverse cardiac remodeling after ischemia-repurfusion. Regulation of EP4 signaling is a potential strategy for protective therapy against cardiac fibrosis. In this study, we show that EP4 signal regulates fibrotic changes and the regulation of signaling pathway in cardiac fibroblast. EP4 agonist decreased the expression of transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF). These results indicated that PGE2-EP4 signaling downregulated the secretion of TGF-β and CTGF in cardiac fibroblast of rat. These results demonstrated that EP4 regulates hormonal factors such as TGF-β and CTGF, resulting in protection of fibrotic changes.

Academic Significance and Societal Importance of the Research Achievements

心臓における線維芽細胞は線維化への関与だけでなく、様々なサイトカインや成長ホルモンを介して心筋細胞に直接作用し、細胞収縮や肥大、さらには細胞生存性を制御することが明らかになっている。プロスタグランディンE2(PGE2)受容体EP4欠損マウスではコントロールと比較し、アンジオテンシンⅡ負荷による心臓の線維化が亢進していることを見出した。我本研究の学術的意義はEP4受容体が、TGF-βを介して心臓線維化の強力な新規調節分子として働いていることを証明し、心臓線維化への作用を解析することである。メカニズムが明らかになることで心臓の線維化を抑制する初めてのEP4作動薬の開発が加速することが期待される。

Research Products

• [Journal Article] Multilayered human skeletal muscle myoblast sheets promote the healing process after colonic anastomosis in rats (2021)
  • Author(s): Nakamura T, Yokoyama U, Kanaya T, Ueno T, Yoda T, Ishibe A, Hidaka Y. Umemura M, Takayama T, Kaneko M, Miyagawa S, Sawa Y, Endo I, Ishikawa Y.
  • Journal Title: Cell Transplantation Volume: 30 Pages: 0-0
  • DOI: 10.1177/09636897211009559
  • Peer Reviewed / Open Access
• [Journal Article] 市販医薬品の薬効成分を磁性化する画期的技術の開発 (2021)
  • Author(s): 梅村 将就,中鍛治 里奈, 永迫 茜, Md Rafikul Islam, 大竹 誠, 長尾 景充, 根本 寛子, 水野 雄斗, 石川 聡一郎, 鈴木 文菜, 石川 義弘
  • Journal Title: 横浜医学 Volume: 72(4) Pages: 537-544
  • NAID: 120007178353
• [Journal Article] ドキソルビシンの心臓線維芽細胞に注目した 心毒性メカニズムの解明と治療戦略 (2021)
  • Author(s): 梅村 将就, 成川 雅俊, 田中 遼, 根本 寛子, 中鍛治 里奈, 永迫 茜, 石川 義弘
  • Journal Title: 日本薬理学雑誌 Volume: 156 Pages: 146-151
  • NAID: 130008032923
• [Journal Article] Excessive EP4 signaling in smooth muscle cells induces abdominal aortic aneurysm by amplifying inflammation (2020)
  • Author(s): Hiromi T, Yokoyama U, Kurotaki D, Mamun A, Ishiwata R, Ichikawa Y, Nishihara H, Umemura M, Fujita T, Yasuda S, Minami T, Goda M, Uchida K, Suzuki S, Takeuchi I, Masuda M, Breyer M, Tamura T, and Ishikawa Y
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 6 Pages: 1559-1573
  • DOI: 10.1161/atvbaha.120.314297
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension (2020)
  • Author(s): Ishigami Tomoaki、Kino Tabito、Minegishi Shintaro、Araki Naomi、Umemura Masanari、Ushio Hisako、Saigoh Sae、Sugiyama Michiko
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 11 Pages: 3871-3871
  • DOI: 10.3390/ijms21113871
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice (2019)
  • Author(s): Prajapati R, Fujita T, Suita K, Nakamura T, Cai W, Hidaka Y, Umemura M, Yokoyama U, Knollmann BC, Okumura S, Ishikawa Y
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 295-303
  • DOI: 10.1253/circj.CJ-18-0743
  • NAID: 130007557004
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive fibrosis precedes doxorubicin-induced heart failure through sterile inflammation. (2019)
  • Author(s): Tanaka R, Umemura M, Narikawa M, Hikichi M, Osaw K, Fujita T, Yokoyama U, Ishigami T, Tamura K, Ishikawa Y.
  • Journal Title: ESC Heart Fail. Volume: 7 Issue: 2 Pages: 588-603
  • DOI: 10.1002/ehf2.12616
  • Peer Reviewed / Open Access
• [Journal Article] Translationally controlled tumor protein (TCTP) plays a pivotal role in cardiomyocyte survival through a Bnip3-dependent mechanism. (2019)
  • Author(s): Cai W, Fujita T, Hidaka Y, Jin H, Suita K, Shigeta M, Kiyonari H, Umemura M, Yokoyama U, Sadoshima J, Ishikawa Y.
  • Journal Title: Cell Death Dis Volume: 10 Issue: 8 Pages: 549-549
  • DOI: 10.1038/s41419-019-1787-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Doxorubicin induces trans-differentiation and MMP1 expression in cardiac fibroblasts via cell death-independent pathways. (2019)
  • Author(s): Narikawa M, Umemura M, Tanaka R, Hikichi M, Nagasako A, Fujita T, Yokoyama U, Ishigami T, Kimura K, Tamura K, Ishikawa Y.
  • Journal Title: PLoS One. Volume: 14 Issue: 9 Pages: e0221940-e0221940
  • DOI: 10.1371/journal.pone.0221940
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin E2 receptor EP4 regulates cell migration through Orai1. (2019)
  • Author(s): Osawa K, Umemura M, Nakakaji R, Tanaka R, Islam RM, Nagasako A, Fujita T, Yokoyama U, Koizumi T, Mitsudo K, Ishikawa Y.
  • Journal Title: Cancer Sci. Volume: 111 Issue: 1 Pages: 160-174
  • DOI: 10.1111/cas.14247
  • Peer Reviewed / Open Access
• [Journal Article] Simultaneous hyperthermia-chemotherapy effect by arterial injection of Fe(Salen) for femur tumor (2018)
  • Author(s): Umemura Masanari、Islam Md. Rafikul、Fukumura Hidenobu、Sato Itaru、Kawabata Yusuke、Matsuo Kousuke、Nakakaji Rina、Nagasako Akane、Ohtake Makoto、Takayuki Fujita、Yokoyama Utako、Nakayama Tomohiro、Eguchi Haruki、Ishikawa Yoshihiro
  • Journal Title: Cancer Science Volume: 110 Issue: 1 Pages: 356-365
  • DOI: 10.1111/cas.13851
  • Peer Reviewed / Open Access
• [Presentation] Innovative Technology of Synthesizing Commercially Available Drugs with Intrinsic Magnetic Property (2022)
  • Author(s): Umemura M
  • Organizer: Innovation in Science, Engineering and Technology (ICISET 2022)
  • Int'l Joint Research / Invited
• [Presentation] Doxorubicin (DOX) Induces Fibrotic Change in Cardiac Fibroblasts (2022)
  • Author(s): Umemura M, Narikawa M, Suzuki F, Nemoto H, Nagasako A, Nakakaji R, Ishikawa Y
  • Organizer: 第98回日本生理学会合同大会 総会・全国学術集会、公募シンポジウム15
• [Presentation] 病態生理の視点からの臓器線維化メカニズムの探索 (2021)
  • Author(s): 梅村将就
  • Organizer: 第126回日本解剖学会・第98回日本生理学会合同大会 総会・全国学術集会、公募シンポジウム
• [Presentation] 静水圧や温熱などの外部刺激に対する心臓繊維芽細胞の生理応答 (2021)
  • Author(s): 梅村将就
  • Organizer: 第126回日本解剖学会・第98回日本生理学会合同大会 総会・全国学術集会
• [Presentation] Doxorubicin induces trans-differentiation in cardiac fibroblasts via cell death-independent pathways (2020)
  • Author(s): Umemura M
  • Organizer: 第93回日本薬理学会年会 公募シンポジウム
• [Presentation] Hydrostatic pressurization suppressed fibrotic change via Akt/GSK-3 signaling in human cardiac fibroblasts (2019)
  • Author(s): Umemura M, Tanaka R, Narikawa M, Ishikawa Y
  • Organizer: The American College of Cardiology (ACC) 2019: 68th Annual Scientific Session & Expo, March 16, New Orleans.
  • Int'l Joint Research
• [Presentation] Doxorubicin directly induced fibrotic change of cardiac fibroblasts and matrix metalloproteinase-1 (2019)
  • Author(s): Narikawa M, Umemura M, Tanaka R, Ishigami T, Tamura K, Ishikawa Y
  • Organizer: The American College of Cardiology (ACC) 2019: 68th Annual Scientific Session & Expo, March 16, New Orleans.
  • Int'l Joint Research
• [Presentation] New technology of Synthesizing Commercial Available Drugs with Intrinsic Magnetism (2019)
  • Author(s): Umemura M, Nakakaji R, Osawa K, Islam R, Eguchi H, Ishikawa Y
  • Organizer: BIT’s 17th Annual Congress of International Drug Discovery Science & Technology, 2019, July, Kyoto, Japan, Invitation Speaker.
  • Int'l Joint Research / Invited
• [Presentation] Prostaglandin E2 receptor EP4 regulates fibrotic changes via intracellular calcium in cardiac fibroblast cells (2019)
  • Author(s): Umemura M, Osawa K, Tanaka R, Hikichi M, Nakakaji R, Ishikawa Y
  • Organizer: American Heart Association (AHA), Scientific Sessions 2019, Philadelphia
  • Int'l Joint Research
• [Remarks] 横浜市立大学大学院医学研究科 循環制御医学
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/gyouseki.html