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Calcific aortic stenosis: Identification of calcification-inducing cell, clarifying calcification signaling

Research Project

Project/Area Number 16K10449
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General surgery
Research InstitutionHirosaki University

Principal Investigator

Seya Kazuhiko  弘前大学, 医学研究科, 助教 (40281919)

Co-Investigator(Kenkyū-buntansha) 古川 賢一  弘前大学, 医学研究科, 准教授 (20165468)
福田 幾夫  弘前大学, 医学研究科, 教授 (50344594)
大徳 和之  弘前大学, 医学部附属病院, 准教授 (50374822)
村上 学  弘前大学, 医学研究科, 教授 (80302090)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords大動脈弁狭窄症 / 異所性石灰化 / 大動脈弁間質細胞 / マトリックスGlaタンパク質 / テネイシンX / 外科 / 薬理学
Outline of Final Research Achievements

Initially, it was confirmed that many of aortic valve interstitial cells (HAVICs) obtained from the aortic valve had characteristics as mesenchymal undifferentiated cells (CD73, 90, 105 (+) / CD45 (-) cells). When hematopoietic stem cell markers, CD34 positive and negative cells were separated from these cells, it was found that CD34 negative cells were sensitive to various calcification stimulations. Microarray analysis of gene expression between CD34 negative and positive cells indicated that low expression of tenascin X (TNX) gene, one of the extracellular matrix proteins, may contribute to the calcification of HAVICs. On the other hand, we confirmed that knockdown of matrix Gla protein (MGP) which is a bone morphogenetic protein 2 antagonist induced spontaneous calcification of HAVICs. These results suggest that knockdown cells of extracellular matrix proteins, TNX and/or MGP, may become calcification-inducing cells in aortic valve.

Academic Significance and Societal Importance of the Research Achievements

・本研究の学術的意義は、異所性石灰化について動脈硬化以外の要因を調べることであり、そのために弁内に存在する未分化細胞に着目して石灰化の原因細胞を明らかにするところにある。
・異所性石灰化機構の解明は、石灰化大動脈弁狭窄症の病態基盤を構築し、石灰化シグナリング機構を抑制する活性物質を礎とした新規薬物治療薬の開発に応用できると共に、高齢者の健康寿命向上に寄与することができることに社会的意義がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (21 results)

All 2019 2018 2017 2016

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 4 results,  Acknowledgement Compliant: 3 results) Presentation (9 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Warfarin calcifies human aortic valve interstitial cells at high-phosphate conditions via pregnane X receptor2019

    • Author(s)
      Yu Zaiqiang、Seya Kazuhiko、Chiyoya Mari、Daitoku Kazuyuki、Motomura Shigeru、Imaizumi Tadaatsu、Fukuda Ikuo、Furukawa Ken-Ichi
    • Journal Title

      Journal of Bone and Mineral Metabolism

      Volume: in oress Issue: 6 Pages: 944-956

    • DOI

      10.1007/s00774-019-01001-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] <b>Gnetin C suppresses double-stranded RNA-induced C-C motif chemokine ligand 2 (CCL2) and CCL5 production by inhibiting Toll-like receptor 3 signaling </b><b>pathway </b>2018

    • Author(s)
      YOSHIDA Hidemi、IMAIZUMI Tadaatsu、MATSUMIYA Tomoh、SEYA Kazuhiko、KAWAGUCHI Shogo、TANAKA Hiroshi
    • Journal Title

      Biomedical Research

      Volume: 39 Issue: 5 Pages: 231-240

    • DOI

      10.2220/biomedres.39.231

    • NAID

      130007498531

    • ISSN
      0388-6107, 1880-313X
    • Year and Date
      2018-10-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] <b>Gnetin C, a resveratrol dimer, reduces amyloid-β 1–42 (Aβ42) production and ameliorates Aβ42-lowered cell viability in cultured SH-SY5Y human neuroblastoma </b><b>cells </b>2018

    • Author(s)
      SEINO Syota、KIMOTO Takeru、YOSHIDA Hidemi、TANJI Kunikazu、MATSUMIYA Tomoh、HAYAKARI Ryo、SEYA Kazuhiko、KAWAGUCHI Shogo、TSURUGA Kazushi、TANAKA Hiroshi、IMAIZUMI Tadaatsu
    • Journal Title

      Biomedical Research

      Volume: 39 Issue: 3 Pages: 105-115

    • DOI

      10.2220/biomedres.39.105

    • NAID

      130007396412

    • ISSN
      0388-6107, 1880-313X
    • Year and Date
      2018-06-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Retinoic acid-inducible gene-I, melanoma differentiation-associated gene 5 and C-X-C motif chemokine ligand 10 are induced by a Toll-like receptor 3 agonist in human brain microvascular endothelial cells2018

    • Author(s)
      Imaizumi Tadaatsu、Arai Akine、Kawaguchi Shogo、Hayakari Ryo、Matsumiya Tomoh、Seya Kazuhiko、Yoshida Hidemi、Tanaka Hiroshi
    • Journal Title

      Clinical and Experimental Neuroimmunology

      Volume: 9 Issue: 3 Pages: 189-197

    • DOI

      10.1111/cen3.12463

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Interferon-stimulated gene 60 (ISG60) constitutes a negative feedback loop in the downstream of TLR3 signaling in hCMEC/D3 cells2018

    • Author(s)
      Imaizumi Tadaatsu、Sassa Naoko、Kawaguchi Shogo、Matsumiya Tomoh、Yoshida Hidemi、Seya Kazuhiko、Shiratori Toshihiro、Hirono Koji、Tanaka Hiroshi
    • Journal Title

      Journal of Neuroimmunology

      Volume: 324 Pages: 16-21

    • DOI

      10.1016/j.jneuroim.2018.08.016

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Matrix Gla protein negatively regulates calcification of human aortic valve interstitial cells isolated from calcified aortic valves2018

    • Author(s)
      Chiyoya Mari、Seya Kazuhiko、Yu Zaiqiang、Daitoku Kazuyuki、Motomura Shigeru、Imaizumi Tadaatsu、Fukuda Ikuo、Furukawa Ken-Ichi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 136 Issue: 4 Pages: 257-265

    • DOI

      10.1016/j.jphs.2018.03.004

    • NAID

      130007812658

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Simultaneous measurement of adenosine 3’,5’-cyclic monophosphate and guanosine 3’,5’-cyclic monophosphate in biological samples.2017

    • Author(s)
      Kazuhiko Seya, Shigeru Motomura, Tadaatsu Imaizumi, Ken-Ichi Furukawa.
    • Journal Title

      Hirosaki Med J

      Volume: 68 Pages: 52-61

    • NAID

      130008036645

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Ketamine suppresses the proliferation of rat C6 glioma cells2017

    • Author(s)
      Niwa Hidetomo、Furukawa Ken-Ichi、Seya Kazuhiko、Hirota Kazuyoshi
    • Journal Title

      Oncology Lett.

      Volume: 14 Issue: 4 Pages: 4911-4917

    • DOI

      10.3892/ol.2017.6806

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Expression of CCL5 is induced by polyinosinic : polycytidylic acid in cultured hCMEC/D3 human brain microvascular endothelial cells2017

    • Author(s)
      Arai Akine、Yoshida Hidemi、Hayakari Ryo、Matsumiya Tomoh、Kawaguchi Shogo、Seya Kazuhiko、Tanaka Hiroshi、Imaizumi Tadaatsu
    • Journal Title

      Clin Exp Neuroimmunol.

      Volume: 8 Issue: 4 Pages: 331-340

    • DOI

      10.1111/cen3.12416

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] 新生仔マウス初代培養心筋細胞の単離培養法2017

    • Author(s)
      韓沖、瀬谷和彦、小潟佳輝、野崎修平、米倉学、村上学
    • Journal Title

      弘前医学

      Volume: 67 Pages: 147-152

    • NAID

      130008038287

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Effects of Enflurane on Cardiac Autonomic Nervous Activity in Mice2017

    • Author(s)
      Yoshiki Ogata, Manabu Yonekura, Rouichi Yamaki, Chong Han, Tomonori Fujisawa, Kazuhiko Seya, Hidetoshi Niwa, Tetsuya Kushikata, Tadaatsu Imaizumi, Kazuyoshi Hirota, Hirofumi Tomita, Manabu Murakami
    • Journal Title

      Hirosaki Medical Journal

      Volume: 67 Pages: 153-157

    • NAID

      130008038285

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] 1-Methyl-2-undecyl-4(1H)-quinidone, a derivative of quinolone alkaloid evocarpine, attenuates high phosphate-induced calcification of human aortic valve interstitial cells by inhibiting phosphate cotransporter PiT-12016

    • Author(s)
      Kazuhiko Seya, Ken-Ichi Furukawa, Mari Chiyoya, Zaiqiang Yu, Haruhisa Kikuchi, Kazuyuki Daitoku, Shigeru Motomura, Manabu Murakami, Yoshiteru Oshima, and Ikuo Fukuda
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 131 Issue: 1 Pages: 51-57

    • DOI

      10.1016/j.jphs.2016.04.013

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 大動脈弁狭窄症患者から得た大動脈弁間質細胞の高リン酸による石灰化誘発に対する1-methyl-2-undecyl-4(1H)-quinoloneの抑制作用2019

    • Author(s)
      瀬谷 和彦、古川 賢一、千代谷真理、于 在強、菊地晴久、大徳和之、元村 成、今泉忠淳、大島吉輝、福田幾夫
    • Organizer
      第48回日本心脈管作動物質学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Matrix Gla protein negatively regulates calcification of human aortic valve interstitial cells isolated from calcified aortic valves2019

    • Author(s)
      Kazuhiko Seya, Zaiqiang Yu, Mari Chiyoya, Wei Yang, Kazuyuki Daitoku, Shigeru Motomura, Tadaatsu Imaizumi, Ikuo Fukuda, Ken-Ichi Furukawa
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 大動脈弁狭窄症患者から得た大動脈弁間質細胞の石灰化に対するマトリックスGlaタンパク質の抑制作用2019

    • Author(s)
      瀬谷和彦 ,于 在強, 千代谷真理, 大徳和之, 元村 成, 今泉忠淳, 福田幾夫, 古川賢一
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] TNF-α-induces calcification of cultured human aortic valve interstitial cells obtained from patients with calcific aortic stenosis: involvement of BMP22018

    • Author(s)
      Kazuhiko Seya, Zaiqiang Yu, Mari Chiyoya, Kazuyuki Daitoku, Shigeru Motomura, Tadaatsu Imaizumi, Ikuo Fukuda, Ken-Ichi Furukawa
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒト石灰化大動脈弁から得た間質細胞においてBMP2が誘発する石灰化に対するワルファリンの影響2018

    • Author(s)
      瀬谷 和彦、于 在強、楊 微、大徳 和之、元村 成、今泉 忠淳、 福田 幾夫、古川 賢一
    • Organizer
      第69回日本薬理学会北部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 石灰化大動脈弁狭窄症患者由来の大動脈弁間質細胞におけるTNF-α誘発性異所性石灰化機序の解明2018

    • Author(s)
      瀬谷 和彦、于 在強、千代谷真理、大徳 和之、元村 成、
    • Organizer
      日本薬学会第138年会(金沢)
    • Related Report
      2017 Research-status Report
  • [Presentation] 大動脈弁に局在する易石灰化性未分化細胞における遺伝的特徴の解析2017

    • Author(s)
      瀬谷和彦、于 在強、野村亜南、千代谷真理、大徳和之、今泉忠淳、元村 成、福田幾夫、古川賢一
    • Organizer
      第68回日本薬理学会北部会(山形)
    • Related Report
      2017 Research-status Report
  • [Presentation] Human aortic valve interstitial cells obtained from patients with calcific aortic stenosis have high sensitivity to TNF-α resulting in ectopic calcification.2017

    • Author(s)
      Kazuhiko Seya, Zaiqiang Yu, Kazuyuki Daitoku, Shigeru Motomura, Tadaatsu Imaizumi, Ikuo Fukuda, Ken-Ichi Furukawa
    • Organizer
      2018 ISHR-JPN Section Meeting (Osaka)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] カルモジュリン依存性プロテインキナーゼIVと交感神経2017

    • Author(s)
      韓沖、野崎修平、小潟佳輝、瀬谷和彦、米倉学、富田泰史、大場貴喜、柳澤輝行、坂上洋行、尾野恭一、村上学
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎市
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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