Regulation of cardiac remodeling by inhibiting the PGD2-mediated inflammatory response.

• Project/Area Number: 16K15199
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: Ikeda Yuichi 東京大学, 医学部附属病院, 特任准教授 (10744419)
• Co-Investigator(Kenkyū-buntansha): 熊谷 英敏 東京大学, 医学部附属病院, 特任助教 (20281008) ; 森田 啓行 東京大学, 医学部附属病院, 講師 (60323573) ; 篠原 正和 神戸大学, 医学(系)研究科(研究院), 研究員 (80437483)
• Co-Investigator(Renkei-kenkyūsha): URADE Yoshihiro 筑波大学, 国際統合睡眠医科学研究機構, 教授 (10201360)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 自己免疫性心筋炎 / 心筋線維化 / プロスタグランディンD2 / H-PGDS阻害薬 / 炎症・免疫 / プロスタグランディン

Outline of Final Research Achievements

Inflammatory response to the cardiomyocyte injury accelerates cardiac remodeling, the pathological process which often determines the clinical course of heart failure. Utilizing the experimental autoimmune myocarditis in mice as a model system, we found that PGD2 produced by H-PGDS contributed to the pathogenesis of cardiac remodeling initiated by local inflammation. In this model, cardiac PGD2 levels were elevated, and the systemic administration of H-PGDS inhibitor decreased the levels of PGD2, resulting in less fibrotic changes in the heart. These findings suggest that inhibition of the local production of PGD2 in the heart is beneficial for suppressing cardiac remodeling. To test if we could generalize our present findings, we established another mouse model based on the mdx mice. Using our second model, we are currently planning to determine if other bioactive lipid mediators produced in the heart are also involved in the pathogenesis of cardiac remodeling.

Research Products

• [Journal Article] A Periodontal pathogen Porphyromonas gingivalis deteriorates Isoproterenol-Induced myocardial remodeling in mice (2017)
  • Author(s): Sato H, Suzuki JI, Aoyama N, Watanabe R, Kaneko M, Shiheido Y, Yoshida A, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M, Izumi Y
  • Journal Title: Hypertens Res. Volume: 40 Issue: 1 Pages: 35-40
  • DOI: 10.1038/hr.2016.114
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction. (2017)
  • Author(s): Watanabe R, Suzuki JI, Wakayama K, Maejima Y, Shimamura M, Koriyama H, Nakagami H, Kumagai H, Ikeda Y, Akazawa H, Morishita R, Komuro I, Isobe M.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 43920-43920
  • DOI: 10.1038/srep43920
  • Peer Reviewed / Open Access
• [Journal Article] Role of Hormone-sensitive Lipase in Leptin-Promoted Fat Loss and Glucose Lowering (2017)
  • Author(s): Takanashi M, Taira Y, Okazaki S, Takase S, Kimura T, Li CC, Xu PF, Noda A, Sakata I, Kumagai H, Ikeda Y, Iizuka Y, Yahagi N, Shimano H, Osuga JI, Ishibashi S, Kadowaki T, Okazaki H
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 11 Pages: 1105-1116
  • DOI: 10.5551/jat.39552
  • NAID: 130006191603
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed
• [Journal Article] Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. (2017)
  • Author(s): Kamo T, Akazawa H, Suda W, Saga-Kamo A, Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT, Takeda N, Harada M, Toko H, Kumagai H, Ikeda Y, Takimoto E, Suzuki JI, Honda K, Morita H, Hattori M, Komuro I.
  • Journal Title: PLoS One. Volume: 12 Issue: 3 Pages: 0174099-0174099
  • DOI: 10.1371/journal.pone.0174099
  • Peer Reviewed / Open Access
• [Journal Article] Generation and characterization of an antagonistic monoclonal antibody against an extracellular domain of mouse DP2 (CRTH2/GPR44) receptors for prostaglandin D2 (2017)
  • Author(s): Nagata N, Iwanari H, Kumagai H, Kusano-Arai O, Ikeda Y, Aritake K, Hamakubo T, Urade Y
  • Journal Title: PLoS One Volume: 12 Issue: 4 Pages: 0175452-0175452
  • DOI: 10.1371/journal.pone.0175452
  • NAID: 120007129138
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Periodontitis deteriorates peripheral arterial disease in Japanese population via enhanced systemic inflammation (2017)
  • Author(s): Aoyama N, Suzuki JI, Kobayashi N, Hanatani T, Ashigaki N, Yoshida A, Shiheido Y, Sato H, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Izumi Y, Isobe M
  • Journal Title: Heart Vessels Volume: 32 Issue: 11 Pages: 1314-1319
  • DOI: 10.1007/s00380-017-1003-6
  • Peer Reviewed
• [Journal Article] Specific periodontopathic bacterial infection affects hypertension in male cardiovascular disease patients (2017)
  • Author(s): Aoyama Norio、Suzuki Jun-ichi、Kumagai Hidetoshi、Ikeda Yuichi、Akazawa Hiroshi、Komuro Issei、Minabe Masato、Izumi Yuichi、Isobe Mitsuaki
  • Journal Title: Heart Vessels. Volume: 33 Issue: 2 Pages: 198-204
  • DOI: 10.1007/s00380-017-1042-z
  • Peer Reviewed
• [Journal Article] Detrimental effects of specific Periodontopathic bacterial infection on tachyarrhythmia compared to Bradyarrhythmia (2017)
  • Author(s): Aoyama Norio、Suzuki Jun-ichi、Kobayashi Naho、Hanatani Tomoya、Ashigaki Norihiko、Yoshida Asuka、Shiheido Yuka、Sato Hiroki、Kumagai Hidetoshi、Ikeda Yuichi、Akazawa Hiroshi、Komuro Issei、Minabe Masato、Izumi Yuichi、Isobe Mitsuaki
  • Journal Title: BMC Cardiovascular Disorders Volume: 17 Issue: 1 Pages: 267-267
  • DOI: 10.1186/s12872-017-0703-2
  • Peer Reviewed / Open Access
• [Journal Article] Three novel BMPR2 mutations associated with advanced pulmonary arterial hypertension (2017)
  • Author(s): Hara Hironori、Takeda Norifumi、Morita Hiroyuki、Hatano Masaru、Amiya Eisuke、Maki Hisataka、Minatsuki Shun、Taki Mizuri、Shiraishi Yasuyuki、Fujiwara Takayuki、Maemura Sonoko、Komuro Issei
  • Journal Title: Human Genome Variation Volume: 4 Issue: 1 Pages: 17010-17010
  • DOI: 10.1038/hgv.2017.10
  • Peer Reviewed
• [Journal Article] A novel mutation of NFIX causes Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection (2017)
  • Author(s): Oshima Tsukasa、Hara Hironori、Takeda Norifumi、Hasumi Eriko、Kuroda Yukiko、Taniguchi Go、Inuzuka Ryo、Nawata Kan、Morita Hiroyuki、Komuro Issei
  • Journal Title: Human Genome Variation Volume: 4 Issue: 1 Pages: 17022-17022
  • DOI: 10.1038/hgv.2017.22
  • Peer Reviewed
• [Journal Article] Omega-3 Polyunsaturated Fatty Acid and Coronary Atherosclerotic Plaques (2017)
  • Author(s): Nakao Tomoko、Morita Hiroyuki
  • Journal Title: International Heart Journal Volume: 58 Issue: 6 Pages: 837-839
  • DOI: 10.1536/ihj.17-552
  • NAID: 130006251669
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Cost-Effectiveness Analysis of Cardiovascular Disease Treatment in Japan (2017)
  • Author(s): Kodera Satoshi、Kiyosue Arihiro、Ando Jiro、Akazawa Hiroshi、Morita Hiroyuki、Watanabe Masafumi、Komuro Issei
  • Journal Title: International Heart Journal Volume: 58 Issue: 6 Pages: 847-852
  • DOI: 10.1536/ihj.17-365
  • NAID: 130006251670
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed
• [Journal Article] Identification of MYLK3 mutations in familial dilated cardiomyopathy (2017)
  • Author(s): Tobita Takashige、Nomura Seitaro、Morita Hiroyuki、Ko Toshiyuki、Fujita Takanori、Toko Haruhiro、Uto Kenta、Hagiwara Nobuhisa、Aburatani Hiroyuki、Komuro Issei
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 17495-17495
  • DOI: 10.1038/s41598-017-17769-1
  • Peer Reviewed / Open Access
• [Journal Article] Safety and Effectiveness of Endovenous Laser Ablation Combined With Ligation for Severe Saphenous Varicose Veins in Japanese Patients (2016)
  • Author(s): Izumi M, Ikeda Y, Yamashita H, Asaoka Y, Fujishiro M, Shin M, Abo Y.
  • Journal Title: International Heart Journal Volume: 57 Issue: 1 Pages: 87-90
  • DOI: 10.1536/ihj.15-282
  • NAID: 130005120984
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Cacao polyphenols ameliorate autoimmune myocarditis in mice (2016)
  • Author(s): Zempo H, Suzuki J, Watanabe R, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M
  • Journal Title: Hypertens Res Volume: 39 Issue: 4 Pages: 203-209
  • DOI: 10.1038/hr.2015.136
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiotensin II receptor blocker irbesartan attenuates cardiac dysfunction induced by myocardial infarction in the presence of renal failure (2016)
  • Author(s): Watanabe R, Suzuki J, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M
  • Journal Title: Hypertens Res Volume: 39 Issue: 4 Pages: 237-244
  • DOI: 10.1038/hr.2015.141
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Toll-like receptor 4 signaling has a critical role in Porphyromonas gingivalis-accelerated neointimal formation after arterial injury in mice. (2016)
  • Author(s): Kobayashi N, Suzuki JI, Aoyama N, Sato H, Akimoto S, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Izumi Y, Isobe M.
  • Journal Title: Hypertens Res Volume: 39 Issue: 10 Pages: 717-722
  • DOI: 10.1038/hr.2016.58
  • Peer Reviewed
• [Journal Article] Projections from single NUCB2/nesfatin-1 neuron in paraventricular nucleus to different brain regions involved in feeding (2016)
  • Author(s): Maejima Y, Kumamoto K, Takenoshita S, Shimomura K
  • Journal Title: Ｂｒａｉｎ Ｓｔｒｕｃｔｕｒｅ ａｎｄ Ｆｕｎｃｔｉｏｎ Volume: ｉｎ ｐｒｅｓｓ Pages: 123-137
  • DOI: 10.1016/j.yjmcc.2016.03.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Periodontitis May Deteriorate Sinus of Valsalva Dilatation in Marfan Syndrome Patients (2016)
  • Author(s): Suzuki J, Imai Y, Aoki M, Fujita D, Takeda N, Aoyama N, Wakayama K, Ikeda Y, Kumagai H, Akazawa H, Izumi Y, Isobe M, Komuro I, Hirata Y
  • Journal Title: International Heart Journal Volume: 57 Issue: 4 Pages: 456-460
  • DOI: 10.1536/ihj.15-395
  • NAID: 130006895913
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Current therapies and investigational drugs for peripheral arterial disease (2016)
  • Author(s): Suzuki J, Shimamura M, Suda H, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Isobe M, Komuro I, Morishita R
  • Journal Title: Hypertens Res Volume: 39 Issue: 4 Pages: 183-191
  • DOI: 10.1038/hr.2015.134
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Understanding vascular diseases: Lessons from premature aging syndromes (2016)
  • Author(s): Ikeda Y, Kumagai H, Motozawa Y, Suzuki J, Akazawa H, Komuro I
  • Journal Title: Can J Cardiol Volume: 32 Issue: 5 Pages: 1-9
  • DOI: 10.1016/j.cjca.2015.12.003
  • Peer Reviewed
• [Journal Article] Current Practices in the Management of Antithrombotic Therapy During the Periendoscopic Period for Patients With Cardiovascular Disease (2016)
  • Author(s): Ono S, Saito I, Ikeda Y, Fujishiro M, Komuro I, Koike K.
  • Journal Title: International Heart Journal Volume: 57 Issue: 5 Pages: 530-534
  • DOI: 10.1536/ihj.16-057
  • NAID: 130005266608
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Growth Differentiation Factor 15 (GDF15) as a Reliable Biomarker for Cardiovascular Risk Assessment (2016)
  • Author(s): Ikeda Y1, Kumagai H, Motozawa Y, Suzuki J
  • Journal Title: International Heart Journal Volume: 57 Issue: 1 Pages: 1-2
  • DOI: 10.1536/ihj.15-324
  • NAID: 130005120988
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Re-bleeding After Endoscopic Hemostasis for Peptic Ulcer Bleeding: Is eNough SAID or Are Other Factors Important? (2016)
  • Author(s): Fujishiro M, Ikeda Y.
  • Journal Title: Dig Dis Sci. Volume: 61 Issue: 6 Pages: 1424-1425
  • DOI: 10.1007/s10620-016-4098-1
  • Peer Reviewed