Elucidation of transcriptional and epigenomic circuit ro reveal molecular mechanisms underlying heart failure and identify novel therapeutic targets

2020 Fiscal Year Annual Research Report

• Project/Area Number: 20H03673
• 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, 医学研究科, 特定准教授 (30467477) ; 元木 博彦 信州大学, 学術研究院医学系, 准教授 (50532058) ; 中川 靖章 京都大学, 医学研究科, 助教 (70452357)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 心不全 / 転写因子 / エピゲノム / 遺伝子

Outline of Annual Research Achievements

本年度は、近年独自に得た新規知見を基に、複合的プロジェクトとして以下の研究を行った。
1. 心筋機能低下におけるCaMK-NRSF-GalphaO circuitの意義の解明。NRSF心筋特異的ノックアウトマウス(NRSF CKO)、以前報告した優性抑制変異NRSF過剰発現マウス(dnNRSF-Tg)を用いた解析により心機能低下におけるGNAO1の意義を新規に見出し、複数の心不全モデルマウスと、GNAO1ノックアウトマウスとの交配やGNAO1心筋特異的過剰発現マウスの解析を通して、その意義と分子機序を解明し、その成果を論文として投稿した（リバイス中）。
2. ヒストン脱アセチル化酵素HDAC1/2を介したCaMK-NRSF転写経路とNotch-Hrt2転写経路のクロストークとその心筋リモデリングにおける意義の解明。心筋特異的誘導性HDAC1/2ダブルノックアウト（HDAC1/2 icKO）、NRSF 心筋特異的誘導性ノックアウトマウス、Hrt2心筋特異的誘導性ノックアウトマウスをそれぞれ作成し、その心臓の表現型および遺伝子発現解析、エピゲノム解析を行った。
3.受容体活性化型カルシウムチャネルTRPC3/6の新規病的心筋リモデリング予防・治療標的としての意義の解明。　複数の心不全モデル（dnNRSF-Tg、圧負荷心不全モデル、troponin I変異DCMモデル、ラミン変異ラットDCMモデル）においてTRPC6あるいはTRPC3ノックアウト、およびTRPC3/6阻害薬の心筋リモデリングや生存率に対する効果を解析した。
4.エピゲノム制御因子LSD1、G9aの心筋恒常性維持における意義の解明。LSD1およびG9aの心筋特異的ノックアウトマウスの表現型解析、遺伝子発現解析を継続した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

上記のように、当初予定していた複数の遺伝子改変モデルの解析を行い、興味深い結果を得ており、現在その分子機序を中心に更なる詳細な解析を進めることができている。加えて一部のデータは論文にまとめ投稿中である。

Strategy for Future Research Activity

1.心筋機能低下におけるCaMK-NRSF-GNAO1 circuitの役割と新規心不全治療標的としての意義の解明。心機能低下におけるGNAO1の意義とその分子機序としてL型カルシウムチャネル活性局在変化が関与することを明らかにし、論文投稿中である。今後はGNAO1がL型カルシウムチャネル活性局在変化を引き起こす詳細なメカニズムの解明を行い、さらなる治療介入点の同定を目指す。
2.HDAC1/2を介したCaMK-NRSF転写経路とNotch-Hrt2転写経路のクロストークとその心筋リモデリングにおける意義の解明。HDAC1/2 icKOが心不全を呈する機序として、その遺伝子発現解析からHDAC1/2の重要なパートナー分子として見出した二つの分子、NRSFとHrt2に関して、それぞれの心筋特異的誘導性ノックアウトマウスを作成しており、これらのマウスの心臓の表現型のさらなる解析と遺伝子発現解析、エピゲノム解析を継続する。
3.受容体活性化型カルシウムチャネルTRPC3/6の新規病的心筋リモデリング予防・治療標的としての意義の解明。本年度TRPC3 KOおよびTRPC6 KOが心不全モデルであるdnNRSF-Tgの生存率を改善する結果を得た。今後はその分子機序の詳細を解析し、加えてTRPC6/3阻害薬であるL862を投与して同様の結果が得られるかを確認する。また圧負荷心不全モデルマウス、ラットラミン変異モデル（DCMモデル）に対してもL862の投与を行っており、その表現型と分子機序の解析を継続する。
4.心筋特異的コンディショナルノックアウトマウスを用いたエピゲノム制御因子LSD1、G9aの心筋恒常性維持における意義の解明。LSD1およびG9aの心筋特異的ノックアウトマウスを作製しその表現型解析を進めており、今後もその解析を継続する。

Research Products

• [Int'l Joint Research] University of Texas/Michigan State University/University of Michigan(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of Texas/Michigan State University/University of Michigan
• [Int'l Joint Research] King’s College London(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: King’s College London
• [Int'l Joint Research] Max-Planck-Institute(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Max-Planck-Institute
• [Journal Article] Impact of nutritional index on long-term outcomes of elderly patients with coronary artery disease: sub-analysis of the SHINANO 5 year registry. (2021)
  • Author(s): Maruyama S, Ebisawa S, Miura T, Yui H, Kashiwagi D, Nagae A, Sakai T, Kato T, Saigusa T, Okada A, Motoki H, Kuwahara K.
  • Journal Title: Heart Vessels Volume: 36 Pages: 7-13
  • DOI: 10.1007/s00380-020-01659-0
  • Peer Reviewed / Open Access
• [Journal Article] Early vascular response of ultra-thin bioresorbable polymer sirolimus-eluting stents assessed by optical frequency domain imaging: the EVALUATION study. (2021)
  • Author(s): Miura T, Ueki Y, Senda K, Otagiri K, Tachibana T, Saigusa T, Ebisawa S, Motoki H, Ikeda U, Kuwahara K
  • Journal Title: Cardiovasc Interv Ther. Volume: in press Pages: in press
  • DOI: 10.1007/s12928-020-00689-9.
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic usefulness of residual SYNTAX score combined with clinical factors for patients with acute coronary syndrome who underwent percutaneous coronary intervention from the SHINANO Registry. (2021)
  • Author(s): Kashiwagi D, Ebisawa S, Yui H, Maruyama S, Nagae A, Sakai T, Kato T, Saigusa T, Okada A, Motoki H, Kuwahara K
  • Journal Title: Heart Vessels Volume: 36 Pages: 170-179
  • DOI: 10.1007/s00380-020-01680-3.
  • Peer Reviewed / Open Access
• [Journal Article] Successful bailout of stent graft stuck in stent occlusion lesion. (2021)
  • Author(s): Kato T, Nagae A, Sakai T, Saigusa T, Ebisawa S, Kuwahara K
  • Journal Title: Cardiovasc Interv Ther Volume: in press Pages: in press
  • DOI: 10.1007/s12928-020-00695-x
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of Spatially-Controlled Vasospasm by Sympathetic Nerve-Mediated ROCK Activation. (2021)
  • Author(s): Imanishi A, Ichise H, Fan C, Nakagawa Y, Kuwahara K, Sumiyama K, Matsuda M, Terai K.
  • Journal Title: Am J Pathol. Volume: 191 Pages: 194-203
  • DOI: 10.1016/j.ajpath.2020.09.012
  • Peer Reviewed
• [Journal Article] Safe and effective transvenous lead extraction for elderly patients utilizing non-laser and laser tools: a single-center experience in Japan. (2021)
  • Author(s): Okada A, Tabata H, Shoda M, Shoin W, Kobayashi H, Okano T, Yoshie K, Kato K, Saigusa T, Ebisawa S, Motoki H, Kuwahara K.
  • Journal Title: Heart Vessels. Volume: 36 Pages: 882-889
  • DOI: 10.1007/s00380-020-01761-3.
  • Peer Reviewed / Open Access
• [Journal Article] Patient Journey and Disease-Related Burden in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension: A Mixed Methods Study. (2021)
  • Author(s): Kinoshita H, Aoki T, Motoki H, Wakita T, Onishi Y, Watanabe-Fujinuma E, Kuwahara K.
  • Journal Title: Value Health Reg Issues. Volume: 24 Pages: 17-23
  • DOI: 10.1016/j.vhri.2020.06.005
  • Peer Reviewed
• [Journal Article] Association of the Prognosis of Ankle-brachial Index Improvement One Year Following Endovascular Therapy in Patients with Peripheral Artery Disease: Data from the I-PAD NAGANO Registry. (2021)
  • Author(s): Senda K, Miura T, Kato T, Kanzaki Y, Abe N, Yokota D, Yanagisawa T, Okina Y, Wakabayashi T, Oyama Y, Karube K, Itagaki T, Yoda H, Shoin K, Oguchi Y, Aizawa K, Suzuki C, Kuwahara K; I-PAD NAGANO registry investigators.
  • Journal Title: Intern Med. Volume: in press Pages: in press
  • DOI: 10.2169/internalmedicine.6117-20.
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of diastolic blood pressure in patients with heart failure with preserved ejection fraction. (2021)
  • Author(s): Fuchida A, Suzuki S, Motoki H, Kanzaki Y, Maruyama T, Hashizume N, Kozuka A, Yahikozawa K, Kuwahara K.
  • Journal Title: Heart Vessels Volume: in press Pages: in press
  • DOI: 10.1007/s00380-021-01788-0.
  • Peer Reviewed / Open Access
• [Journal Article] Serum cholinesterase as a prognostic biomarker for acute heart failure. (2021)
  • Author(s): Shiba M, Kato T, Morimoto T, Yaku H, Inuzuka Y, Tamaki Y, Ozasa N, Seko Y, Yamamoto E, Yoshikawa Y, Kitai T, Yamashita Y, Iguchi M, Nagao K, Kawase Y, Morinaga T, Toyofuku M, Furukawa Y, Ando K, Kadota K, Sato Y, Kuwahara K, Kimura T.
  • Journal Title: Eur Heart J Acute Cardiovasc Care. Volume: in press Pages: in press
  • DOI: 10.1093/ehjacc/zuaa043.
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic value of reduction in left atrial size during a follow-up of heart failure: an observational study (2021)
  • Author(s): Shiba M, Kato T, Morimoto T, Yaku H, Inuzuka Y, Tamaki Y, Ozasa N, Seko Y, Yamamoto E, Yoshikawa Y, Kitai T, Yamashita Y, Iguchi M, Nagao K, Kawase Y, Morinaga T, Toyofuku M, Furukawa Y, Ando K, Kadota K, Sato Y, Kuwahara K, Kimura T; KCHF Study Investigators
  • Journal Title: BMJ Open Volume: 11 Pages: e044409.
  • DOI: 10.1136/bmjopen-2020-044409
  • Peer Reviewed / Open Access
• [Journal Article] Successful hot balloon ablation for focal atrial tachycardia derived from the left superior pulmonary vein antrum. (2020)
  • Author(s): Tabata H, Okada A, Kobayashi H, Shoin W, Okano T, Yoshie K, Motoki H, Shoda M, Kuwahara K
  • Journal Title: J Arrhythm Volume: 36 Pages: 368-370
  • DOI: 10.1002/joa3.12313.
  • Peer Reviewed / Open Access
• [Journal Article] Sodium-Glucose Cotransporter-2 inhibitors are potential therapeutic agents for treatment of non-diabetic heart failure patients. (2020)
  • Author(s): Nakagawa Y, Kuwahara K
  • Journal Title: J Cardiol Volume: 76 Pages: 123-131
  • DOI: 10.1016/j.jjcc.2020.03.009.
  • Peer Reviewed / Open Access
• [Journal Article] Rationale and Design of the EMPYREAN Study: Investigation on the Effect of Empagliflozin on Cardiac Sympathetic and Parasympathetic Nerve Activity in Japanese Patients with Type 2 Diabetes. (2020)
  • Author(s): Motoki H, Masuda I, Yasuno S, Oba K, Shoin W, Usami S, Saito Y, Waki M, Komatsu M, Ueshima K, Nakagawa Y, Son C, Yonemitsu S, Hiramitsu S, Konda M, Onishi K, Kuwahara K.
  • Journal Title: ESC Heart Failure Volume: 7 Pages: 3134-3141
  • DOI: 10.1002/ehf2.12825
  • Peer Reviewed / Open Access
• [Journal Article] Impact of changes in body mass index after percutaneous coronary intervention on long-term outcomes in patients with coronary artery disease. (2020)
  • Author(s): Yui H, Ebisawa S, Miura T, Nakamura C, Maruyama S, Kashiwagi D, Nagae A, Sakai T, Kato T, Saigusa T, Okada A, Motoki H, Kuwahara K
  • Journal Title: Heart Vessels Volume: 35 Pages: 1657-1663
  • DOI: 10.1007/s00380-020-01648-3
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic impact of mineralocorticoid receptor antagonist in patients with heart failure with preserved ejection fraction. (2020)
  • Author(s): Suzuki S, Motoki H, Kanzaki Y, Maruyama T, Hashizume N, Kozuka A, Yahikozawa K, Kuwahara K.
  • Journal Title: ESC Heart Fail Volume: 7 Pages: :2752-2761
  • DOI: 10.1002/ehf2.12867
  • Peer Reviewed / Open Access
• [Journal Article] Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo. (2020)
  • Author(s): Ichimura H, Kadota S, Kashihara T, Yamada M, Ito K, Kobayashi H, Tanaka Y, Shiba N, Chuma S, Tohyama S, Seto T, Okada K, Kuwahara K, Shiba Y.
  • Journal Title: Sci Rep Volume: 10 Pages: 11883
  • DOI: 10.1038/s41598-020-68373-9
  • Peer Reviewed / Open Access
• [Journal Article] Sex differences in patients with acute decompensated heart failure in Japan: observation from the KCHF registry (2020)
  • Author(s): Yamamoto E, Kato T, Yaku H, Morimoto T, Inuzuka Y, Tamaki Y, Ozasa N, Komasa A, Nishikawa R, Kawase Y, Morinaga T, Kawato M, Seko Y, Toyofuku M, Furukawa Y, Nakagawa Y, Ando K, Kadota K, Shizuta S, Ono K, Sato Y, Kuwahara K, Kimura T, et al.
  • Journal Title: ESC Heart Fail. Volume: 7 Pages: 2485-2493
  • DOI: 10.1002/ehf2.12815
  • Peer Reviewed / Open Access
• [Journal Article] Impact of left ventricular ejection fraction on the effect of renin-angiotensin system blockers after an episode of acute heart failure: From the KCHF Registry. (2020)
  • Author(s): Yoshikawa Y, Tamaki Y, Morimoto T, Yaku H, Yamamoto E, Inuzuka Y, Ozasa N, Kitai T, Nagao K, Sato Y, Kondo H, Tamura T, Nakagawa Y, Kuwahara K, Kato T, Kimura T.
  • Journal Title: PLoS One Volume: 15 Pages: e0239100
  • DOI: 10.1371/journal.pone.0239100.
  • Peer Reviewed / Open Access
• [Journal Article] Association between body mass index and prognosis of patients hospitalized with heart failure. (2020)
  • Author(s): Seko Y, Kato T, Morimoto T, Yaku H, Inuzuka Y, Tamaki Y, Ozasa N, Shiba M, Yamamoto E, Yoshikawa Y, Yamashita Y, Kitai T, Taniguchi R, Iguchi M, Nagao K, Kawai T, Komasa A, Nishikawa R, Kawase Y, Morinaga T, Toyofuku M, Furukawa Y, Ando K, Kadota K, Sato Y, Kuwahara K, Kimura T
  • Journal Title: Sci Rep Volume: 10 Pages: 16663
  • DOI: 10.1038/s41598-020-73640-w.
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy. (2020)
  • Author(s): Docherty KF, Jhund PS, Bengtsson O, DeMets DL, Inzucchi SE, Kosiborod MN, Langkilde AM, Martinez FA, Sabatine MS, Solomon SD, McMurray JJV, et al; DAPA-HF Investigators and Committees
  • Journal Title: Diabetes Care Volume: 43 Pages: 2878-2881
  • DOI: 10.2337/dc20-1402
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cardio-renal and cardio-hepatic interactions predict cardiovascular events in elderly patients with heart failure (2020)
  • Author(s): Okano T, Motoki H, Minamisawa M, Kimura K, Kanai M, Yoshie K, Higuchi S, Saigusa T, Ebisawa S, Okada A, Shoda M, Kuwahara K.
  • Journal Title: PLoS One Volume: 15 Pages: e0241003.
  • DOI: 10.1371/journal.pone.0241003.
  • Peer Reviewed / Open Access
• [Journal Article] "Alpha"-Looped Broken Pacemaker Lead Inside the Heart. (2020)
  • Author(s): Tabata H, Okada A, Kobayashi H, Shoin W, Okano T, Yoshie K, Motoki H, Shoda M, Kuwahara K.
  • Journal Title: Circ J Volume: 85 Pages: 77.
  • DOI: 10.1253/circj.CJ-20-0680
  • Peer Reviewed / Open Access
• [Journal Article] Association of an increase in serum albumin levels with positive 1-year outcomes in acute decompensated heart failure: A cohort study. (2020)
  • Author(s): Kato T, Yaku H, Morimoto T, Inuzuka Y, Tamaki Y, Ozasa N, Yamamoto E, Yoshikawa Y, Kitai T, Taniguchi R, Iguchi M, Kato M, Takahashi M, Jinnai T, Ikeda T, Nagao K, Kawai T, Komasa A, Nishikawa R, Kawase Y, Morinaga T, Kawato M, Seko Y, Shiba M, Toyofuku M, Furukawa Y, Ando K, Kadota K, Sato Y, Kuwahara K, Kimura T.
  • Journal Title: PLoS One Volume: 15 Pages: e0243818
  • DOI: 10.1371/journal.pone.0243818.
  • Peer Reviewed / Open Access
• [Journal Article] C-reactive protein at discharge and 1-year mortality in hospitalised patients with acute decompensated heart failure: an observational study. (2020)
  • Author(s): Nishimoto Y, Kato T, Morimoto T, Yaku H, Inuzuka Y, Tamaki Y, Yamamoto E, Kuwahara K, Ozasa N, Sato Y, Kimura T, et al.
  • Journal Title: BMJ Open. Volume: 10 Pages: e041068.
  • DOI: 10.1136/bmjopen-2020-041068.
  • Peer Reviewed / Open Access
• [Journal Article] Rationale and Design of Therapeutic Angiogenesis by Cell Transplantation Using Adipose-Derived Regenerative Cells in Patients With Critical Limb Ischemia - TACT-ADRC Multicenter Trial. (2020)
  • Author(s): Shimizu Y, Kondo K, Fukumoto Y, Takamura M, Inoue T, Nagata T, Akashi YJ, Yamada Y, Kuwahara K, Kobayashi Y, Shibata R, Murohara T; TACT-ADRC Multicenter Trial Group.
  • Journal Title: Circ Rep Volume: 2 Pages: 531-535
  • DOI: 10.1253/circrep.CR-20-0055.
  • Peer Reviewed / Open Access
• [Presentation] TRPC6/3 are Potential Therapeutic Targets for the Treatment of Pulmonary Arterial Hypertension (2021)
  • Author(s): Kuwahara K
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Why are They Effective?: Mechanisms Underlying Novel Therapeutic Agents for Heart Failure (2021)
  • Author(s): Kuwahara K
  • Organizer: 第85回日本循環器学会学術集会
  • Invited
• [Presentation] Heart Failure and Diabetes: Clinical Relevance and Perspectives in the Prevention and Treatment. (2021)
  • Author(s): Kuwahara K
  • Organizer: 第85回日本循環器学会学術集会
  • Invited
• [Presentation] Implication of Natriuretic Peptides in Cardio-Renal Interactions (2021)
  • Author(s): Kuwahara K
  • Organizer: 第85回日本循環器学会学術集会
  • Invited
• [Presentation] Sacubitril Valsartan in the Treatment of Heart Failure: From the Basic to the Clinical Perspectives (2021)
  • Author(s): Kuwahara K
  • Organizer: 第85回日本循環器学会学術集会
  • Invited
• [Presentation] Impact of Polypharmacy on Adherence and Prognosis in Patients with Acute Decompensated Heart Failure: From CURE-HF Registry (2021)
  • Author(s): Kanai M, Motoki H, Okano T, Kimura K, Minamisawa M, Yoshie K, Kato T, Saigusa T, Ebisawa S, Okada A, Kuwahara K.
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Gender Difference in Heart Failure with Preserved Ejection Fraction: Clinical Profiles, Examinations, and Prognosis (2021)
  • Author(s): Sakai T, Motoki H, Minamisawa M, Kimura K, kanai M, Saigusa T, Ebisawa S, Yoshie K, Okada A, Kuwahara K
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Impact of Polyparmacy on Adherence and Prognosis in Patients with Acute Decompensated Heart Failure: From CURE-HF Registry (2020)
  • Author(s): Motoki H, Yamaguchi R, Okano T, Kimura K, Minamisawa M, Yoshie K, Kato T, Saigusa T, Ebisawa S, Okada A, Kuwahara K.
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] 糖尿病と心不全予防を兼ねるSGLT2阻害薬 (2020)
  • Author(s): Kuwahara K.
  • Organizer: 第84回日本循環器学会学術集会
  • Invited
• [Presentation] The Impact of Multiple Medications on Long-term Prognosis in Patients with Acute Decompensated HF-insights from the KCHF Registry (2020)
  • Author(s): Ozasa N, Kato T, Morimoto T, Yaku H, Yamamoto E, Inuzuka Y, Tamaki Y, Yoshikawa Y, Sato Y, Kuwahara K, Kimura T
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] 心不全診療の現状と課題 (2020)
  • Author(s): 桑原宏一郎
  • Organizer: 第147回日本内科学会信越地方会
  • Invited
• [Presentation] 新しい心不全治療薬(SGLT2i、ARNI、Ivabradin)は何をよりどころにして処方すべきか． (2020)
  • Author(s): 桑原宏一郎
  • Organizer: 第24回日本心不全学会学術集会
  • Invited
• [Presentation] Novel players in Ca2＋ -dependent signaling pathway (2020)
  • Author(s): 桑原宏一郎
  • Organizer: CVMW2020
  • Invited
• [Book] Encyclopedia of Molecular Pharmacology (Editors: Stefan Offermanns and Walter Rosenthal) (2021)
  • Author(s): Yasuaki Nakagawa, Koichiro Kuwahara
  • Total Pages: 1510
  • Publisher: Springer
  • ISBN: 978-3-030-57400-0
• [Remarks] 信州大学医学部循環器内科 ホームページ
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/department/doctor/zouki/i-oreg/cardiovascular/