Elucidation of epigenetic regulation of gene expresson involved in maintaining cardiac function and metabolism

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26293187
• Research Institution: Shinshu University
• Principal Investigator: 桑原 宏一郎 信州大学, 学術研究院医学系, 教授 (30402887)
• Co-Investigator(Kenkyū-buntansha): 木下 秀之 京都大学, 医学(系)研究科(研究院), 准教授 (30467477) ; 中川 靖章 京都大学, 医学(系)研究科(研究院), 助教 (70452357)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 分子心臓学 / 転写因子 / 遺伝子 / エピゲノム / シグナル伝達経路

Outline of Annual Research Achievements

本研究では、不全心において特徴的に認められる遺伝子発現変化に関わる転写・エピジェネティック調節経路の解明を通した慢性心不全の分子病態解明と、新規治療標的・戦略の同定・構築をめざす。本年度は昨年度から引き続き以下の研究を行った。1), 心筋特異的NRSFコンディショナルノックアウトマウス(CKO)の表現系解析及びその分子機構解明。昨年度までの研究で心筋特異的NRSFノックアウトマウスおよび優性抑制変異NRSF心筋特異的過剰発現マウス(dnNRSF-Tg)の心機能低下にGaphaOタンパクをコードするGNAO1遺伝子の発現亢進の関与を見出し、上記2系統のマウスとGNAO1ノックアウトマウスの交配を行い、その心機能の改善を確認した。その分子機序として、T管以外の細胞脈表面からのCaイオン流入の変化が関与していることを見出した。またGNAO1遺伝子上にNRSEを同定し、GNAO1がNRSFの直接の標的分子であること、また圧負荷心モデルの左室においてGNAO1発現が亢進していることを確認した。2)Rho依存性転写活性化因子MRTF-Aの病的心筋リモデリングにおける意義の解析とそれに基づく新規心不全予防・治療薬開発。より選択性の高いMRTF-A阻害薬開発を共同研究で引き続き進めると同時に、心不全マウスであるdnNRSF-TgとMRTF-Aノックアウトマウスとの交配を行い、解析を継続した。3)新規心不全治療標的としてのTRPC6/3イオンチャネルの意義の解明。 TRPC阻害薬を心不全モデルマウスであるdnNRSF-Tgに投与し、その心機能改善効果の解析を継続して行った。またTRPC3/6ダブルノックアウトマウスとdnNRSF-Tgとの交配を行い、その心機能解析も行った。同時に肺高血圧モデルにおいてTRPC阻害薬、TRPC3/6ノックアウトは肺動脈圧上昇を減少させることを見出した。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Causes of Carryover

28年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

28年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] The University of Texas/Michigan State University(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: The University of Texas/Michigan State University
• [Journal Article] MiR30-GALNT1/2 axis-mediated glycosylation contributes to the increased secretion of inactive human pro-BNP from failing hearts. (2017)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Fujishima A, Oka S, Tsutamoto T, Kinoshita H, Nakao K, Cho K, Inazumi H, Okamoto H, Nishida M, Kato T, Fukushima H, Yamashita J, Wijnen WJ, Creemers EE, Kangawa K, Minamino N, Nakao K, Kimura T.
  • Journal Title: J Am Heart Assoc Volume: 6 Pages: e0003601
  • DOI: 10.1161/JAHA.116.003601
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Endothelium-derived C-type natriuretic peptide contributes to blood pressure regulation by maintaining endothelial integrity. (2017)
  • Author(s): Nakao K, Kuwahara K, Nishikimi T, Nakagawa Y, Kinoshita H, Minami T, Kuwabara Y, Yamada C, Yamada Y, Tokudome T, Nagai-Okatani C, Minamino N, Nakao YM, Yasuno S, Ueshima K, Sone M, Kimura T, Kangawa K, Nakao K
  • Journal Title: Hypertension. Volume: 69 Pages: 286-296
  • DOI: 10.1161/HYPERTENSIONAHA.116.08219
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diagnostic advantage of stress computed tomography myocardial perfusion over single-photon emission computed tomography for the assessment of myocardial ischemia. (2017)
  • Author(s): Ueki Y, Izawa A, Kashiwagi D, Nishiyama S, Aso S, Suzuki C, Sakurai S, Oguchi K, Yazaki Y, Ikeda U, Kuwahara K.
  • Journal Title: J Cardiol Volume: 印刷中 Pages: -
  • DOI: 10.1016/j.jjcc.2016.11.004.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prevention of abdominal aortic aneurysm progression by oral administration of green tea polyphenol in a rat model. (2017)
  • Author(s): Setozaki S, Minakata K, Masumoto H, Hirao S, Yamazaki K, Kuwahara K, Ikeda T, Sakata R.
  • Journal Title: J Vasc Surg Volume: 65 Pages: 1803-1812
  • DOI: 10.1016/j.jvs.2016.06.003
  • Peer Reviewed
• [Journal Article] Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy. (2017)
  • Author(s): Mori KP, Yokoi H, Kasahara M, Imamaki H, Ishii A, Kuwabara T, Koga K, Kato Y, Toda N, Ohno S, Kuwahara K, Endo T, Nakao K, Yanagita M, Mukoyama M, Mori K.
  • Journal Title: J Am Soc Nephrol. Volume: 28 Pages: 278-289
  • DOI: 10.1681/ASN.2015101168
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis (2016)
  • Author(s): Numaga-Tomita T, Kitajima N, Kuroda T, Nishimura A, Miyano K, Yasuda S, Kuwahara K, Sato Y, Ide T, Birnbaumer L, Sumimoto H, Mori Y, Nishida M
  • Journal Title: Sci Rep Volume: 6 Pages: 39383.
  • DOI: 10.1038/srep39383.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clinical Characteristics and Outcomes of Patients with High Ankle-Brachial Index from the IMPACT-ABI Study (2016)
  • Author(s): Nishimura H, Miura T, Minamisawa M, Ueki Y, Abe N, Hashizume N, Mochidome T, Harada M, Shimizu K, Shoin W, Yoshie K, Oguchi Y, Ebisawa S, Motoki H, Izawa A, Koyama J, Ikeda U, Kuwahara K.
  • Journal Title: PLoS One Volume: 11 Pages: e0167150
  • DOI: 10.1371/journal.pone.0167150
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Brain Natriuretic Peptide Counteracting the Renin-angiotensin-aldosterone System in Accelerated Malignant Hypertension (2016)
  • Author(s): Nakagawa H, Mizuno Y, Harada E, Morikawa Y, Kuwahara K, Saito Y, Yasue H
  • Journal Title: Am J Med Sci Volume: 352 Pages: 534-539
  • DOI: 10.1016/j.amjms.2016.08.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling (2016)
  • Author(s): Kitajima N, Numaga-Tomita T, Watanabe M, Kuroda T, Nishimura A, Miyano K, Yasuda S, Kuwahara K, Sato Y, Ide T, Birnbaumer L, Sumimoto H, Mori Y, Nishida M
  • Journal Title: Sci Rep. Volume: 6 Pages: 37001
  • DOI: 10.1038/srep37001
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure. (2016)
  • Author(s): Ohno S, Yokoi H, Mori K, Kasahara M, Kuwahara K, Fujikura J, Naito M, Kuwabara T, Imamaki H, Ishii A, Saleem MA, Numata T, Mori Y, Nakao K, Yanagita M, Mukoyama M
  • Journal Title: Sci Rep Volume: 6 Pages: 27192
  • DOI: 10.1038/srep27192
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The renin-angiotensin system promotes arrhythmogenic substrates and lethal 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, Junko Shibata J, Nakao K, Cho K, Arai Y, Honjo H, Kamiya K, Nakao K and Kimura T
  • Journal Title: Cardiovasc Res Volume: 109 Pages: 162-73
  • DOI: 10.1093/cvr/cvv248
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Secretion of proBNP is regulated by MiR30-GALNTs axis dependent O-linked glycosylation in the pathological myocardium (2016)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Kinoshita H, Inazumi H, Moriuchi K, Kato T, Minamino N, Nakao K, Kimura T
  • Organizer: AHA Scientific Session 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-11-13 – 2016-11-16
  • Int'l Joint Research
• [Presentation] MiR30-GALNT1/2 axis-mediatede glycosylation regulates the increase in inactive human pro-BNP secretion from failing heart. (2016)
  • Author(s): Kuwahara K, Nakagawa Y, Nishikimi T, Kinoshita H, Okamoto H, Kato T, Kangawa K, Minamino N, Nakao K, Kimura T
  • Organizer: Hypertension Seoul 2016, The 26th Scientific meeting of the International Society of Hypertension
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-09-24 – 2016-09-29
  • Int'l Joint Research
• [Presentation] Unprocessed proBNP secretion is regulated by MiR30-GALNTs axis dependent O-glycosylation in the pathological myocardium. (2016)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Kinoshita H, Yamada C, Inazumi H, Nakao K, Kimura T
  • Organizer: AHA BCVS2016
  • Place of Presentation: Phoenix, Arizona, USA
  • Year and Date: 2016-07-18 – 2016-07-21
  • Int'l Joint Research
• [Presentation] MiR30-GALNT1/2 axis-mediated glycosylation at threonine 48 and 71 plays an essential role in the increased secretion of unprocessed pro-brain natriuretic peptide by failing hearts (2016)
  • Author(s): Kuwahara K, Nakagawa Y, Nishikimi T, Kangawa K, Minamino N, Nakao K, Kimura T.
  • Organizer: Heart Failure 2016
  • Place of Presentation: Florence, Italy
  • Year and Date: 2016-05-21 – 2016-05-24
  • Int'l Joint Research
• [Presentation] MiR30-GALNTs axis-mediated O-glycosylation plays an important role in the increased secretion of unprocessed pro-brain natriuretic peptide by failing heart (2016)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Nakao K and Kimura T
  • Organizer: Keystone symposia
  • Place of Presentation: Snowbird, Utah, USA
  • Year and Date: 2016-04-03 – 2016-04-07
  • Int'l Joint Research
• [Book] Endocrinology of the Heart in Health and Disease (2016)
  • Author(s): Nishikimi T, Kuwahara K, Nakagawa Y, Kangawa K, and Nakao K
  • Total Pages: 378(41-58)
  • Publisher: Elsevier Scinence
• [Remarks] 信州大学医学部循環器内科学教室
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/department/doctor/zouki/i-oreg/cardiovascular/