The elucidation of the role of chronic inflammation in heart failure.

• Project/Area Number: 24390064
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Shitennoji University (2014); Osaka City University (2012-2013)
• Principal Investigator: IWAO Hiroshi 四天王寺大学, 教育学部, 教授 (00137192)
• Co-Investigator(Kenkyū-buntansha): IZUMI Yasukatsu 大阪市立大学, 大学院医学研究科, 准教授 (10347495)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: マクロファージ / エクソソーム / 心リモデリング / 内皮細胞 / HIF-1alpha / HSP70

Outline of Final Research Achievements

Hypertension is one of the most important cardiovascular risk factors, and results in macrophage infiltration into the tissues. Here, we investigated the role of exosome, one of extracellular vesicles, in the inflammatory pathways of endothelial cells (ECs) under hypertensive conditions.
Exosomes were purified by ultracentrifugation. The exosomes isolated from angiotensin II-infused rat serum abundantly contained macrophage marker proteins, CD68 and CD45. Moreover, exosomes from hypertensive rat serum immediately activated intracellular signals such as c-jun N-terminal kinase and p38 mitogen-activated protein kinase, and upregulated the expression of intracellular adhesion molecule-1 in ECs. Interestingly, exosomes from THP-1-derived macrophages stimulated by Angiotensin II also activated these signaling pathways in ECs.
These results suggest that macrophage-derived exosomes under hypertensive conditions activate the inflammatory pathway in ECs, leading to cardiovascular remodeling.

Research Products

• [Journal Article] Myeloid HIF-1 attenuates the progression of renal fibrosis in murine obstructive nephropathy. (2015)
  • Author(s): Tateishi,Y, Osada-Oka M, Tanaka M, Shiota M, Izumi Y, Ishimura E, Motoyama K, Inaba M, Miura, K.
  • Journal Title: J Pharmacol Sci Volume: 127 Issue: 2 Pages: 181-189
  • DOI: 10.1016/j.jphs.2014.12.011
  • Peer Reviewed / Open Access
• [Journal Article] Percutaneous Carbon Dioxide Treatment using a Gas Mist Generator Enhances the Collateral Blood Flow in the Ischemic Hindlimb (2015)
  • Author(s): Izumi, Y
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 22 Issue: 1 Pages: 38-51
  • DOI: 10.5551/jat.23770
  • NAID: 130004677973
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Percutaneous carbon dioxide mist treatment has protective effects in experimental myocardial infarction. (2015)
  • Author(s): Yamaguchi T, Yamazaki T, Nakamura Y, Shiota M, Shimada K, Miura K, Iwao H, Yoshiyama M, Izumi Y.
  • Journal Title: J Pharmacol Sci Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction (2014)
  • Author(s): Yamaguchi, T
  • Journal Title: Int J Cardiol Volume: 30 Pages: 239-246
  • DOI: 10.1016/j.ijcard.2014.10.144
  • Peer Reviewed / Open Access
• [Journal Article] A Noninvasive Metabolic Syndrome Model Using an Extremely Small Minipig, the Microminipig (2014)
  • Author(s): Yamaguchi, T
  • Journal Title: Journal of Pharmacological Sciences Volume: 126 Issue: 2 Pages: 168-171
  • DOI: 10.1254/jphs.14171SC
  • NAID: 130004690915
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of neutralizing rat monoclonal antibodies for fibroblast growth factor-2 (2014)
  • Author(s): Tanaka M, Yamaguchi M, Shiota M, Kawamoto Y, Takahashi K, Inagaki A, Osada-Oka M, Harada A, Wanibuchi H, Izumi Y, Miura K, Iwao H, Ohkawa Y.
  • Journal Title: Monoclon Antib Immunodiagn Immunother Volume: 33 Issue: 4 Pages: 261-269
  • DOI: 10.1089/mab.2013.0085
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hsc70 contributes to cancer cell survival by preventing Rab1A degradation under stress conditions. (2014)
  • Author(s): Tanaka M, Mun S, Harada A, Ohkawa Y, Inagaki A, Sano S, Takahashi K, Izumi Y, Osada-Oka M, Wanibuchi H, Yamagata M, Yukimura T, Miura K, Shiota M, Iwao H.
  • Journal Title: PLoS One Volume: 9 Issue: 5 Pages: e96785-e96785
  • DOI: 10.1371/journal.pone.0096785
  • Peer Reviewed / Open Access
• [Journal Article] Lipid synthesis is promoted by hypoxic adipocyte-derived exosomes in 3T3-L1cells (2014)
  • Author(s): Sano S, Izumi Y, Yamaguchi T, Yamazaki T, Tanaka M, Shiota M, Osada-Oka M, Nakamura Y, Wei M, Wanibuchi H, Iwao H, Yoshiyama M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 445 Issue: 2 Pages: 327-33
  • DOI: 10.1016/j.bbrc.2014.01.183
  • Peer Reviewed
• [Journal Article] Therapeutic Potential of Vasopressin-Receptor Antagonists in Heart Failure (2014)
  • Author(s): Izumi Y, Miura K, Iwao H.
  • Journal Title: Journal of Pharmacological Sciences Volume: 124 Issue: 1 Pages: 1-6
  • DOI: 10.1254/jphs.13R13CP
  • NAID: 130003382634
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Establishment of a 5-fluorouracil-resistant triple-negative breast cancer cell line (2013)
  • Author(s): Takahashi K, Tanaka M, Inagaki A, Wanibuchi H, Izumi Y, Miura K, Nagayama K, Shiota M, Iwao H.
  • Journal Title: Int J Oncol. Volume: 43 Issue: 6 Pages: 1985-91
  • DOI: 10.3892/ijo.2013.2135
  • Peer Reviewed
• [Journal Article] Tolvaptan Attenuates Left Ventricular Fibrosis After Acute Myocardial Infarction in Rats (2013)
  • Author(s): Yamazaki T, Nakamura Y, Shiota M, Osada-Oka M, Fujiki H, Hanatani A, Shimada K, Miura K, Yoshiyama M, Iwao H, Izumi Y.
  • Journal Title: Journal of Pharmacological Sciences Volume: 123 Issue: 1 Pages: 58-66
  • DOI: 10.1254/jphs.13086FP
  • NAID: 10031202963
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Drug-Induced Takotsubo Cardiomyopathy. (2013)
  • Author(s): Izumi Y.
  • Journal Title: Heart Failure Clinics Volume: 9 Issue: 2 Pages: 225-231
  • DOI: 10.1016/j.hfc.2012.12.004
• [Journal Article] Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2. (2012)
  • Author(s): Shiota M, Hikita Y, Kawamoto Y, Kusakabe H, Tanaka M, Izumi Y, Nakao T, Miura K, Funae Y Iwao H
  • Journal Title: J Cell Mol Med. Volume: 16 Pages: 2001-2009
  • Peer Reviewed
• [Journal Article] Angiotensin AT1 receptor blockers suppress oxidized low-density lipoprotein-derived formation of foam cells. (2012)
  • Author(s): Osada-Oka M, Kita H, Yagi S, Sato T, Izumi Y, Iwao H
  • Journal Title: Eur J Pharmacol. Volume: 679 Issue: 1-3 Pages: 9-15
  • DOI: 10.1016/j.ejphar.2011.12.044
  • Peer Reviewed
• [Journal Article] Novel device that produces carbon dioxide mist for myocardial infarction treatment in rats. (2012)
  • Author(s): Yamazaki T, Izumi Y, Nakamura Y, Hanatani A, Shimada K, Muro T, Shiota M, Iwao H, Yoshiyama M
  • Journal Title: Circ J. Volume: 76 Pages: 1203-1212
  • NAID: 10030132718
  • Peer Reviewed
• [Journal Article] Red ginseng inhibits scratching behavior associated with atopic dermatitis in experimental animal models. (2012)
  • Author(s): Samukawa K, Izumi Y Shiota M, Nakao T, Osada-Oka M, Miura K, Iwao H.
  • Journal Title: J Pharmacol Sci. Volume: 118 Pages: 391-400
  • NAID: 10030455761
  • Peer Reviewed
• [Journal Article] Tolvaptan improves left ventricular dysfunction after myocardial infarction in rats. (2012)
  • Author(s): Yamazaki T, Izumi y Nakamura Y, Yamashita N, Fujiki H, Osada-Oka M, Shiota M, Hanatani A, Shimada K, Iwao H, Yoshiyama M.
  • Journal Title: Circ Heart Fail. Volume: 5 Issue: 6 Pages: 794-802
  • DOI: 10.1161/circheartfailure.112.968750
  • Peer Reviewed
• [Presentation] レニン･アンジオテンシン系研究と心血管病 (2015)
  • Author(s): 岩尾 洋
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
  • Invited
• [Presentation] エクソソームを介した心血管疾患制御 (2015)
  • Author(s): 泉 康雄、山口 雄大、岡 真優子、塩田 正之、田中 昌子、三浦 克之、岩尾 洋
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Stromal cell-derived factor 2はoxaliplatin耐性に寄与する (2015)
  • Author(s): 高橋 克之、田中 昌子、塩田 正之、泉 康雄、三浦 克之、岩尾 洋
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 四肢の虚血コンディショニングはエクソソームを介した情報伝達によって心リモデリングを抑制する (2015)
  • Author(s): 山口 雄大、葭山 稔、塩田 正之、田中 昌子、三浦 克之、岩尾 洋、泉 康雄
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 低血清・低酸素耐性膵癌細胞におけるゲムシタビン感受性の評価 (2015)
  • Author(s): 市坪 大将、田中 昌子、高橋 克之、泉 康雄、塩田 正之、岩尾 洋、三浦 克之
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 紅蔘エキスによる好塩基球のp70S6キナーゼ阻害と抗アレルギー作用 (2015)
  • Author(s): 岡 真優子、平井 沙也花、南山 幸子、寒川 慶一、岩尾 洋、泉 康雄
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 一過性の遠隔部虚血コンディショニングはエクソソームを介して心保護作用を発揮する (2014)
  • Author(s): 泉 康雄、山口 雄大、岡 真優子、田中 昌子、塩田 正之、葭山 稔、三浦 克之、岩尾 洋
  • Organizer: 第24回日本循環薬理学会
  • Place of Presentation: 山形テルサ（山形県・山形市）
  • Year and Date: 2014-12-05
• [Presentation] 膵癌細胞における低血清・酸素耐性株の樹立と 膵癌細胞における低血清・酸素耐性株の樹立とGemcitabone感受性の評価 (2014)
  • Author(s): 市坪 大将、田中 昌子、髙橋 克之、泉 康雄、塩田正之、三浦克之、岩尾 洋
  • Organizer: 第126回日本薬理学会近畿部会
  • Place of Presentation: 和歌山県JAビル（和歌山県・和歌山市）
  • Year and Date: 2014-10-24
• [Presentation] 超小型ミニブタを用いたメタボリック症候群モデルの作製 (2014)
  • Author(s): 泉 康雄、中村 泰浩、山崎 貴紀、島田 健永、葭山 稔、岩尾 洋
  • Organizer: 第37回日本高血圧学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-10-17 – 2014-10-19
• [Presentation] 活性化マクロファージ由来エキソソームと血管内皮細胞障害 (2014)
  • Author(s): 岡 真優子、塩田正之、田中昌子、泉 康雄、岩尾 洋
  • Organizer: 第87回 日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Exosome-mediated intercellular communication by repetitive remote ischemic conditioning reduces left ventricular remodeling on chronic heart failure. (2014)
  • Author(s): Takehiro Yamaguchi, Yasukatsu Izumi, Takanori Yamazaki, Yasuhiro Nakamura, Soichi Sano, Akihisa Hanatani, Kenei Shimada, Hiroshi Iwao, Minoru Yoshiyama
  • Organizer: European Society of Cardiology Scientific Session 2014
  • Place of Presentation: Barcelona Convention Centre（バルセロナ・スペイン）
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Repetitive treatment of percutaneous carbon dioxide mist prevents high fat diet-induced arteriosclerosis in extremely small size minipig. (2014)
  • Author(s): Yasukatsu Izumi, Takehiro Yamaguchi, Hiroaki Kawaguchi, Masashi Tawa, Takanori Yamazaki, Masayuki Shiota, Akihide Tanimoto, Tomio Okamura, Minoru Yoshiyama, Hiroshi Iwao
  • Organizer: European Society of Cardiology Scientific Session 2014
  • Place of Presentation: Barcelona Convention Centre（バルセロナ・スペイン）
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Macrophage-derived exosomes damage endothelial cells in experimental hypertensive models. (2014)
  • Author(s): Yasukatsu Izumi, Takehiro Yamaguchi, Mayuko Osada-Oka, Masayuki Shiota, Masako Tanaka, Soichi Sano, Minoru Yoshiyama, Hiroshi Iwao
  • Organizer: European Society of Cardiology Scientific Session 2014
  • Place of Presentation: Barcelona Convention Centre（バルセロナ・スペイン）
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] 慢性心不全に対するremote ischemic conditioning効果 (2014)
  • Author(s): 泉 康雄、山口 雄大、岡 真優子、塩田 正之、田中 昌子、葭山 稔、三浦 克之、岩尾 洋
  • Organizer: 第125回日本薬理学会近畿部会
  • Place of Presentation: 岡山コンベンションセンター（岡山県・岡山市）
  • Year and Date: 2014-06-20
• [Presentation] The role of macrophage-derived exosomes in hypertension. (2014)
  • Author(s): Takehiro Yamaguchi, Hiroshi Iwao, Mayuko Osada-Oka, Masayuki Shiota, Masako Tanaka, Katsuyuki Miura, Minoru Yoshiyama, Yasukatsu Izumi
  • Organizer: European Society of Hypertension/International Society of Hypertension 2014
  • Place of Presentation: Megaron Athens International Cnferebce Centre（アテネ・ギリシャ）
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] A nitric oxide synthase inhibitor accelerates high fat diet-induced arteriosclerosis in extremely small size minipig, Microminipig. (2014)
  • Author(s): Yasukatsu Izumi, TakehiroYamaguchi, Takanori Yamazaki, Hiroaki Kawaguchi, Masashi Tawa, Masayuki Shiota, Akihide Tanimoto, Tomio Okamura, Minoru Yoshiyama, Hiroshi Iwao
  • Organizer: 第18回国際血管生物学会
  • Place of Presentation: 都メッセ京都（京都府・京都市）
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] 慢性心不全に対する一過性四肢虚血コンディショニング効果 (2014)
  • Author(s): 泉 康雄、山口 雄大、山崎 貴紀、中村 泰浩、岡 真優子、塩田 正之、葭山 稔、岩尾 洋
  • Organizer: 第43回 日本心脈管作動物質学会
  • Place of Presentation: 神戸国際会議場(兵庫県)
• [Presentation] The establishment of a noninvasive metabolic syndrome model using an extremely small size minipig, Microminipig (2014)
  • Author(s): 泉 康雄、山口 雄大、川口 博明、田和 正志、塩田 正之、岡 真優子、谷本 昭英、岡村 富夫、三浦 克之、岩尾 洋
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター(宮城県)
• [Presentation] Endothelial cell dysfunction via hypoxia macrophage-derived exosomes (2014)
  • Author(s): 岡 真優子、西山 方規、泉 康雄、塩田 正之、田中 昌子、三浦 克之、岩尾 洋
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター(宮城県)
• [Presentation] 心血管病克服に向けた新たなパラダイム (2013)
  • Author(s): 岩尾洋
  • Organizer: 第42回 日本心脈管作動物質学会
  • Place of Presentation: 奈良(招待講演)
  • Year and Date: 2013-02-08
• [Presentation] ラット心筋梗塞急性期および慢性期に対するバソプレシンV_2受容体拮抗薬の有効性 (2013)
  • Author(s): 泉康雄
  • Organizer: 第42回 日本心脈管作動物質学会
  • Place of Presentation: 奈良
  • Year and Date: 2013-02-08
• [Presentation] アンジオテンシンIIによるエクソソームへの影響 (2013)
  • Author(s): 西山方規
  • Organizer: 第42回 日本心脈管作動物質学会
  • Place of Presentation: 奈良
  • Year and Date: 2013-02-08
• [Presentation] 超小型ミニブタを用いた、非侵襲的メタボリック症候群モデルの作製 (2013)
  • Author(s): 泉 康雄、川口 博明、田和 正志、山崎 貴紀、山口 雄大、岡 真優子、塩田 正之、葭山 稔、谷本 昭英、岡村 富夫、岩尾 洋
  • Organizer: 第４９回高血圧関連疾患モデル学会
  • Place of Presentation: 日本大学会館(東京都)
• [Presentation] 高血圧におけるエキソソームの役割 (2013)
  • Author(s): 泉 康雄、岡 真優子、塩田 正之、岩尾 洋
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪国際会議場(大阪府）
• [Presentation] Beneficial effects of repeated remote ischemic conditioning on chronic heart failure at chronic phase after myocardial infarction (2013)
  • Author(s): Takehiro Yamaguchi, Yasukatsu Izumi, Takanori Yamazaki, Yasuhiro Nakamura, Soichi Sano, Akihisa Hanatani, Kenei Shimada, Hiroshi Iwao, Minoru Yoshiyama
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: ダラスコンベンションセンター(米国)
• [Presentation] 高血圧モデルにおけるマクロファージ由来エキソソームの内皮への影響 (2013)
  • Author(s): 泉 康雄、岡 真優子、西山 方規、田中 昌子、山口 雄大、塩田 正之、岩尾 洋
  • Organizer: 第17回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府)
• [Presentation] エクソソームを介した高血圧症による血管機能障害 (2012)
  • Author(s): 岡真優子
  • Organizer: 第122回 日本薬理学会近畿部会
  • Place of Presentation: 大阪
  • Year and Date: 2012-11-16