Elucidation of pathophysiological significance of glycosylation in the regulatory mechanism of BNP processing

• Project/Area Number: 25461107
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: NAKAGAWA YASUAKI 京都大学, 医学(系)研究科(研究院), 助教 (70452357)
• Co-Investigator(Kenkyū-buntansha): KUWAHARA KOICHIRO 京都大学, 大学院医学研究科, 講師 (30402887) ; KUWAHARA KOICHIRO 京都大学, 大学院医学研究科, 非常勤講師 (80291946)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 分子心臓病学 / 分子心臓学

Outline of Final Research Achievements

O-linked glycosylation in both Thr48 and Thr71 on N-terminal region of proBNP, which is an procursor peptide of brain natriuretic peptide(BNP), plays an essential role, and glycosylation in other sites also indirectly affects in the regulatory mechanisms of processing and secretion of proBNP in the cardiac myocytes.

Research Products

• [Journal Article] The renin-angiotensin system promotes arrhythmogenic substrates andalethal arrhythmias in mice with non-ischemic cardiomyopathy (2016)
  • Author(s): Yamada C, Kuwahara K, Yamazaki M, Nakagawa Y, Nishikimi T, Kinoshita H, Kuwabara Y, Minami T, Yamada Y, Shibata J, Nakao K, , Arai Y, Honjo H, Kamiya K, Nakao K, Kimura T
  • Journal Title: Cardiovascular Research Volume: 109 Issue: 1 Pages: 162-173
  • DOI: 10.1093/cvr/cvv248
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential Relationships Between Anemia and Outcome in Subgroups of Patients With Chronic Heart Failure (2015)
  • Author(s): Nakagawa Y, Yasuno S, Kuwahara K
  • Journal Title: Circulation Journal Volume: 79 Issue: 9 Pages: 1893-1894
  • DOI: 10.1253/circj.CJ-15-0852
  • NAID: 130005095294
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pro-B-type natriuretic peptide is cleaved intracellularly: impact of distance between O-glycosylation and cleavage sites. (2015)
  • Author(s): Nishikimi T, Nakagawa Y, Minamino N, Ikeda M, Tabei K, Fujishima A, Takayama K, Akimoto K, Yamada C, Nakao K, Minami T, Kuwabara Y, Kinoshita H, Tsutamoto T, Ishimitsu T, Kangawa K, Kuwahara K, Nakao K
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. Volume: 309
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure. (2014)
  • Author(s): Yamada Y, Kinoshita H, Kuwahara K, Nakagawa Y, Kuwabara Y, Minami T, Yamada C, Shibata J, Nakao K, Cho K, Arai Y, Yasuno S, Nishikimi T, Ueshima K, Kamakura S, Nishida M, Kiyonaka S, Mori Y, Kimura T, Kangawa K, Nakao K.
  • Journal Title: Cardiovasc Research Volume: 104 Issue: 1 Pages: 183-193
  • DOI: 10.1093/cvr/cvu185
  • NAID: 120005619790
  • Peer Reviewed / Open Access
• [Journal Article] The effects of super-flux (high performance) dialyzer on plasma glycosylated pro-B-type natriuretic peptide (proBNP) and glycosylated N-Terminal proBNP in end-stage renal disease patients on dialysis. (2014)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Yasuno S, Kinoshita H, Kuwabara Y, Nakao K, Minami T, Yamada C, Ueshima K, Ikeda Y, Okamoto H, Horii K, Nagata K, Kangawa K, Minamino N, Nakao K.
  • Journal Title: PLoS One Volume: 25 Issue: 3 Pages: e92314-e92314
  • DOI: 10.1371/journal.pone.0092314
  • NAID: 120007100132
  • Peer Reviewed / Open Access
• [Journal Article] Identification of chemicals inducing cardiomyocyte proliferation in developmental stage-specific manner with pluripotent stem cells (2013)
  • Author(s): Uosaki H, Magadum A, Seo K, Fukushima H, Takeuchi A, Nakagawa Y, Moyes KW, Narazaki G, Kuwahara K, Laflamme M, Matsuoka S, Nakatsuji N, Nakao K, Kwon C, Kass DA, Engel FB, Yamashita JK
  • Journal Title: Circ Cardiovasc Genet Volume: 6(6) Issue: 6 Pages: 624-33
  • DOI: 10.1161/circgenetics.113.000330
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy (2013)
  • Author(s): Yasuno, S., Kuwahara, K., Kinoshita, H., Yamada, C., Nakagawa, Y., Usami, S., Kuwabara, Y., Ueshima, K., Harada, M., Nishikimi, T., Nakao, K.
  • Journal Title: British Journal of Pharmacology Volume: 170(7) Issue: 7 Pages: 1384-1395
  • DOI: 10.1111/bph.12328
  • Peer Reviewed
• [Journal Article] Adrenomedullin in cardiovascular disease: a useful biomarker, its pathological roles and therapeutic application. (2013)
  • Author(s): Nishikimi T, Kuwahara K, Nakagawa Y, Kangawa K, Nakao K.
  • Journal Title: Curr Protein Pept Sci. Volume: 14(4) Pages: 256-67
  • Peer Reviewed
• [Journal Article] Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts. (2013)
  • Author(s): Kuwabara, Y., Kuwahara, K., Takano, M., Kinoshita, H., Arai, Y., Yasuno, S., Nakagawa, Y., Igata, S., Usami, S., Minami, T., Yamada, Y., Nakao, K., Yamada, C., Shibata, J., Nishikimi, T., Ueshima, K., Nakao, K.
  • Journal Title: Journal of the American Heart Association Volume: 2(3) Issue: 3
  • DOI: 10.1161/jaha.113.000150
  • Peer Reviewed
• [Presentation] Mir-30-GALNTs axis-mediated regulation in glcosylation and secretion of proBNP in the failing heart (2016)
  • Author(s): Yasuaki Nakagawa , Toshio Nishikimi, Koichiro Kuwahara, Naoto Minamino, Takao Kato, Hideyuki Kinoshita, Chinatsu Yamada, Hideaki Inazumi, Kazuwa Nakao, Takeshi Kimura
  • Organizer: 第80回 日本循環器学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] BNP; too high, too low (2016)
  • Author(s): 中川靖章
  • Organizer: 第80回日本循環器学会学術集会ファイアサイドセミナー
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] MiR-30-GALNT経路による糖鎖修飾制御が病的心におけるproBNP分泌増加に関与する (2015)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、木下秀之、柴田純子、山田千夏、稲住英明、加藤貴雄、南野直人、中尾一和、木村剛
  • Organizer: 第10回高血圧と冠動脈疾患研究会
  • Place of Presentation: 大手町サンケイプラザ（東京）
  • Year and Date: 2015-12-19
• [Presentation] 心不全患者におけるproBNPの分泌と代謝についての検討 (2015)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、木下秀之、山田千夏、南野直人、中尾一和、木村剛
  • Organizer: 第19回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 神戸国際会議場（神戸）
  • Year and Date: 2015-12-10
• [Presentation] O型糖鎖修飾を介したヒトBNPプロセシング調節に関与する糖転移酵素についての検討 (2015)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、木下秀之、山田千夏、南野直人、中尾一和、木村剛
  • Organizer: 第19回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 神戸国際会議場（神戸）
  • Year and Date: 2015-12-10
• [Presentation] 心室筋でのBNP産生におけるproBNP N端末O型糖鎖修飾の意義 (2015)
  • Author(s): 中川靖章、桑原宏一郎、錦見俊雄、木村剛
  • Organizer: 第2回iHFフォーラム
  • Place of Presentation: 都市センターホテル（東京）
  • Year and Date: 2015-08-08
• [Presentation] O-glycosylation in N-terminal region of proBNP regulates its processing in ventricular myocytes (2014)
  • Author(s): Yasuaki Nakagawa, Toshio Nishikimi, Koichiro Kuwahara, Shinji Yasuno, Hideyuki Kinoshita, Yoshihiro Kuwabara, Chinatsu Yamada, Kenji Ueshima, Naoto Minamino, Kazuwa Nakao, Takeshi Kimura,
  • Organizer: 第31会 国際心臓研究会(ISHR)日本部会
  • Place of Presentation: ウインクあいち、愛知県
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] ヒトproBNPプロセシングにおけるＯ型糖鎖修飾の意義についての検討 (2014)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、山田千夏、上嶋健治、南野直人、中尾一和、木村剛
  • Organizer: 第18回日本心血管内分泌代謝学会学術集会
  • Place of Presentation: 横浜、神奈川
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] Role of O-glycosylation in N-terminal region of human proBNP in its processing mechanisms (2014)
  • Author(s): Yasuaki Nakagawa, Toshio Nishikimi, Koichiro Kuwahara, Shinji Yasuno, Hideyuki Kinoshita, Yoshihiro Kuwabara, Kazuhiro Nakao, Chinatsu Yamada, Kenji Ueshima, Naoto Minamino, Takeshi Kimura, Kazuwa Nakao
  • Organizer: AHA Scientific Sessoins 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] 拡張型心筋症モデルマウスにおけるN型Ca2+チャネル阻害は自律神経バランスを改善し突然死を予防する (2014)
  • Author(s): 桑原宏一郎、山田優子、木下秀之、中川靖章、柴田純子、山田千夏、森泰生、中尾一和、木村剛
  • Organizer: 第37回 日本高血圧学会総会
  • Place of Presentation: 横浜、神奈川
  • Year and Date: 2014-10-17 – 2014-10-19
• [Presentation] Role of O-glycosylation in N-terminal region of human proBNP in proBNP processing (2014)
  • Author(s): Yasuaki Nakagawa, Toshio Nishikimi, Koichiro Kuwahara, Shinji Yasuno, Hideyuki Kinoshita, Yoshihiro Kuwabara, Kazuhiro Nakao, Chinatsu Yamada, Kenji Ueshima, Naoto Minamino, Takeshi Kimura, Kazuwa Nakao
  • Organizer: 第18回日本心不全学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-10 – 2014-10-12
• [Presentation] Significance of O-glycosylation in proBNP processing (2014)
  • Author(s): Yasuaki Nakagawa, Toshio Nishikimi, Koichiro Kuwahara, Shinji Yasuno, Hideyuki Kinoshita, Yoshihiro Kuwabara, Kazuhiro Nakao, Chinatsu Yamada, Kenji Ueshima, Naoto Minamino, Takeshi Kimura, Kazuwa Nakao,
  • Organizer: The Conference on Bioactive Peptide for Cell-Cell Communication 2014
  • Place of Presentation: 京都
  • Year and Date: 2014-09-10 – 2014-09-12
• [Presentation] Critical involvement of renin-angiotensin system for developing arrhythmogenic remodeling in mice with chronic heart failure and lethal arrhythmias (2014)
  • Author(s): C. Yamada, K. Kuwahara, Y. Kuwabara, H. Kinoshita, Y. Nakagawa, T. Nihikimi, K. Nakao, T. Kimura
  • Organizer: ESC 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Increased Expression of HCN channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts (2014)
  • Author(s): Yoshihiro Kuwabara, Koichiro Kuwahara, Makoto Takano, Hideyuki Kinoshita, Yuji Arai, Yasuaki Nakagawa, Shinji Ysuno, Sachiyo Igata, Satoru Usami, Takeya Minami, Yuko Yamada, Kazuhiro Nakao, Chinatsu Yamada, Junko Shibata, Toshio Nishikimi,Kenji Ueshima, Kazuwa Nakao
  • Organizer: 第31回日本心電学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-22 – 2014-07-25
• [Presentation] C-type Natriuretic Peptide Derived from Vascular Endothelial Cells Contributes to the Regulation of Blood Pressure (2014)
  • Author(s): Nakao K, Kuwahara K, Nishikimi T, Nakagawa Y, Kinoshita H, Tokudome T, Sone M, Kimura T, Kangawa,K and Nakao K
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-18
• [Presentation] Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodeling in mice (2014)
  • Author(s): Minami T, Kuwahara K, Kuwabara Y, Cho K, Kinoshita H, Nakagawa Y, Ueda K, Kimura T.
  • Organizer: The 18th International Vascular Biology M
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-18
• [Presentation] 脳性(B型)ナトリウム利尿ペプチド前駆体proBNPプロセシングにおける糖鎖結合の役割 (2014)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、木下秀之、桒原佳宏、山田千夏、中尾一泰、保野慎治、上嶋健治、木村剛、南野直人、中尾一和
  • Organizer: 第51回 日本臨床分子医学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-11 – 2014-04-12
• [Presentation] Elucidation of molecular mechanism of human proBNP:role of O-glycosylation in N-terminal region of proBNP (2014)
  • Author(s): Yasuaki Nakagawa, Toshio Nishikimi, Koichiro Kuwahara, Shinji Yasuno, Hideyuki Kinoshita, Yoshihiro Kuwabara, Kazuhiro Nakao, Chinatsu Yamada, Kenji Ueshima, Naoto Minamino, Takeshi Kimura, Kazuwa Nakao
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] 透析患者における血中N端proBNPの糖鎖修飾と測定系への影響について (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: 第２回臨床高血圧フォーラム
  • Place of Presentation: JPタワーホール＆カンファレンス
• [Presentation] Effect of O-linked Glycosylation of plasma N-terminal proBNP on NT-proBNP assay in hemodyalysis patients (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: 心筋代謝研究会
  • Place of Presentation: キャノンマーケティングジャパン株式会社3階ホール
• [Presentation] Effect of hemodyalysis on precursor proBNP and glycosylated NT-proBNP in end-stage renal disease patients. (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: ESC congress 2013
  • Place of Presentation: アムステルダム
• [Presentation] 透析患者における血中B型（脳性）ナトリウム利尿ペプチド前駆体proBNPについての検討 (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: 第61回心臓病学会
  • Place of Presentation: ホテル日航熊本、鶴屋ホール
• [Presentation] 透析中の末期腎不全患者における血中proBNPについての検討 (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: 第36回日本高血圧学会
  • Place of Presentation: 大阪国際会議場
• [Presentation] 維持血液透析患者における血中B型（脳性）ナトリウム利尿ペプチド前駆体 (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: 第17回日本心血管内分泌代謝学会
  • Place of Presentation: 千里ライフサイエンスセンター
• [Presentation] 維持血液透析患者におけるproBNPについての検討 (2013)
  • Author(s): 中川靖章、錦見俊雄、桑原宏一郎、保野慎治、木下秀之、桒原佳宏、中尾一泰、山田千夏、上嶋健治、中尾一和
  • Organizer: 第17回日本心不全学会学術集会
  • Place of Presentation: 大宮ソニックシティ
• [Remarks] 京都大学医学部付属病院循環器内科 心血管内分泌代謝グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/cat236/