Elucidation of significance of vascular CNP-GC-B system in vascular integrity and pathology

• Project/Area Number: 26670400
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: Kuwahara Koichiro 京都大学, 医学(系)研究科(研究院), 講師 (30402887)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ナトリウム利尿ペプチド / 血管内皮 / 血圧 / 循環器

Outline of Final Research Achievements

In this study, we studied the role of vascular CNP-GC-B system in vascular homeostasis. We generated vascular endothelial cell-specific CNP knockout (CNP ecKO) mice and measured blood pressures in these CNP ecKO mice. CNP ecKO mice showed significantly higher blood pressure than control mice. In CNP ecKO, endothelium-dependent vasorelaxation was impaired and endothelial expression of vasoconstrictive endothelin-1 was increased. By contrast, vascular smooth muscle cell-specific GC-B knockout (GC-B smcKO) mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.

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 Issue: 6 Pages: R639-R649
  • DOI: 10.1152/ajpregu.00074.2015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The local CNP/GC-B system in the growth plate is responsible for physiological endochondral bone growth. (2015)
  • Author(s): Nakao, K., Osawa, K., Yasoda, A., Yamanaka, S., Fujii, T., Kondo, E., Koyama, N., Kanamoto, N., Miura, M., Kuwahara, K., Akiyama, H., Bessho, K., and Nakao, K..
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 1-11
  • DOI: 10.1038/srep10554
  • NAID: 120007100129
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The organ-protective effect of N-type Ca(2+) channelblockade. (2015)
  • Author(s): Kuwahara K, Kimura T.
  • Journal Title: Pharmacol Ther. Volume: 15 Pages: 00045-5
  • DOI: 10.1016/j.pharmthera.2015.02.001
  • NAID: 120005663276
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model. (2015)
  • Author(s): Tanaka M, Yamaguchi S, Yamazaki Y, Kinoshita H, Kuwahara K, Nakao K, Jay PY, Noda T, Nakamura T.
  • Journal Title: Science Report Volume: 5 Issue: 1 Pages: 7826-7826
  • DOI: 10.1038/srep07826
  • NAID: 120007100130
  • Peer Reviewed / Open Access
• [Journal Article] Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2. (2015)
  • Author(s): Oshita K, Itoh M, Hirashima S, Kuwabara Y, Ishihara K, Kuwahara K, Nakao K, Kimura T, Nakamura K, Ushijima K, Takano M.
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 80 Pages: 81-89
  • DOI: 10.1016/j.yjmcc.2014.12.019
  • NAID: 120007100131
  • Peer Reviewed / Open Access
• [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
• [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集会
  • Place of Presentation: 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集会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] MiR30-GALNT axis-mediated regulation of glycosylation participates in the secretion of proBNP in failing hearts (2015)
  • Author(s): 桑原宏一郎、中川靖章、錦見俊雄、中尾一和、木村剛
  • Organizer: 第32回 国際心臓学会日本部会 (ISHR 2015)
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] 心不全進展にかかわる心筋遺伝子転写調節分子経路の解明 (2015)
  • Author(s): 桑原宏一郎
  • Organizer: 第19回 日本心不全学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-22
  • Invited
• [Presentation] NRSF plays an essential role in the regulation of cardiac gene expression and function (2015)
  • Author(s): 桑原宏一郎
  • Organizer: 第58回 日本神経化学会大会
  • Place of Presentation: 大宮
  • Year and Date: 2015-09-11
  • Invited
• [Presentation] N-type Ca2+ channels blockade restores the cardiac autonomic balance and prevents lethal arrhythmias in mice with dilated cardiomyopathy (2015)
  • Author(s): Koichiro Kuwahara, Yuko Yamada, Hideyuki Kinoshita, Yasuaki Nakagawa, Kazuwa Nakao and Takeshi Kimura
  • Organizer: 25th European Meeting on Hypertension and Cardiovascular Protection (European Society of Hypertension)
  • Place of Presentation: ミラノ
  • Year and Date: 2015-06-12
  • Int'l Joint Research
• [Presentation] Ion channel remodeling in the progression of heart failure (2015)
  • Author(s): 桑原宏一郎
  • Organizer: 第79回 日本循環器学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
  • Invited
• [Presentation] 心機能の破綻と維持における転写調節経路の解明～心不全新規治療法の探索～ (2015)
  • Author(s): 桑原宏一郎
  • Organizer: 第52回 日本臨床分子医学会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10
  • Invited
• [Presentation] 心不全に伴う不整脈突然死発症にかかわる分子メカニズム (2015)
  • Author(s): 桑原宏一郎、中尾一和、木村剛
  • Organizer: 第44回 日本心脈管作動物質学会
  • Place of Presentation: 高松
  • Year and Date: 2015-02-06 – 2015-02-07
  • Invited
• [Presentation] 心血管系におけるナトリウム利尿ペプチドの産生制御と作用機序の新知見 (2014)
  • Author(s): 桑原宏一郎
  • Organizer: 第18回日本心血管内分泌代謝学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-21 – 2014-11-22
  • Invited
• [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
  • 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
  • Year and Date: 2014-10-17 – 2014-10-19
• [Presentation] Pivotal involvement of renin-angiotensin system in promoting arrhythmogenic remodeling in (2014)
  • Author(s): Chinatsu Yamada, Koichiro Kuwahara, Hideyuki Kinoshita,Yasuaki Nakagawa, Toshio Nishikimi Kazuwa Nakao, Takeshi Kimura
  • Organizer: 第18回日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-10 – 2014-10-12
• [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
  • 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] 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
• [Book] ガイドライン外来診療2014 心不全の項 (2014)
  • Author(s): 桑原宏一郎、木村剛
  • Total Pages: 620
  • Publisher: 日経メディカル開発
• [Remarks] 京都大学医学部付属病院循環器内科学 心血管内分泌代謝研究室
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/cat236/
• [Remarks] 研究室ホームページ
  • URL: http://www.kuhp.kyoto-u.ac.jp/~med2/jpn/research/cardio.html
• [Remarks] 京都大学循環器内科ホームページ
  • URL: http://kyoto-u-cardio.jp/