抗加齢に着目した難治性心不全に対する新しい治療法の開発

2012 Fiscal Year Research-status Report

• Project/Area Number: 24591100
• Research Category: Grant-in-Aid for Scientific Research (C)
• Research Institution: Fukushima Medical University
• Principal Investigator: 竹石 恭知 福島県立医科大学, 医学部, 教授 (40272067)
• Co-Investigator(Kenkyū-buntansha): 及川 雅啓 福島県立医科大学, 医学部, 助教 (30457775) ; 鈴木 聡 福島県立医科大学, 医学部, 助教 (60536944)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 加齢 / 心不全 / 酸化ストレス / ドキソルビシン / アポトーシス / 遺伝子操作マウス

Research Abstract

Senescence marker protein-30 (SMP30)は、ノックアウトマウス(SMP30-KO)の解析から抗酸化作用、抗アポトーシス作用を有し、抗加齢蛋白として機能していることが示唆されている。心不全の発症と進展に酸化ストレスやアポトーシスが深く関与していることが広く認識されている。SMP30 は抗酸化作用、抗アポトーシス作用を有し、心不全の発症と病態の進展を抑制する可能性があるが、これまで心臓においてはSMP30 の機能については十分に検討されていない。我々は SMP30 遺伝子を心臓にのみ選択的に過剰発現したトランスジェニックマウス(SMP30-TG)を作成した。SMP30-TG マウスと SMP30-KO マウスのフェノタイプを詳細に対比することで、SMP30 の心臓での機能を in vivo で検討する。本研究では、SMP30 の心不全の発症と進展における役割を明らかにし、抗加齢という観点から新しい心不全治療戦略を確立することを目的とした。
今年度はドキソルビシン(DOX) による心機能低下における SMP30 の役割を検討した。１２週齢の野生型(WT)マウス、SMP30-KO マウスの腹腔内に DOX 20 mg/kg ないし生食を投与した。DOX 投与１週間後、心エコー検査を行い、サクリファイスし心臓を摘出した。SMP30-KO マウスでは、WT マウスと比べて DOX 投与後の左室駆出率は低下し、線維化は増加、superoxide 産生は増加、8OHdG 陽性細胞数、TUNEL 陽性細胞数は増加、caspase-3 活性、Bax/Bcl-2 比、JNK 活性は上昇した。SMP30-KO マウスでは DOX による心機能低下が増悪し、酸化ストレスによるアポトーシスシグナルの活性化を認め、SMP30 の心保護作用が示唆された。

Current Status of Research Progress

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

Reason

ドキソルビシン心筋症の発症機序のひとつに SMP30 が関与している可能性を KO マウスを用いて明らかにした。

Strategy for Future Research Activity

実験補助員の確保が難しく謝金が少なくなった、マウスの繁殖が予定どおりいかずに飼育費が少なかった、等により次年度に使用する研究費が生じた。しかし、その後状況は改善し、研究は順調に遂行されている。

Expenditure Plans for the Next FY Research Funding

次年度分の研究費と合わせて、計画に沿って適切に使用する予定である。
物品費　1,645,154（Ｈ２４年度分　645,154　＋　Ｈ２５年度分　1,000,000）
旅費　　 100,000
謝金　　 424,000（Ｈ２４年度分　124,000　＋　Ｈ２５年度分　300,000）

Research Products

• [Journal Article] A reduction of coronary flow reserve is associated with chronic kidney disease and long-term cardio-cerebrovascular events in patients with non-obstructive coronary artery disease and vasospasm (2012)
  • Author(s): Sakamoto N, Iwaya S, Owada T, Nakamura Y, Yamauchi H, Hoshino Y, Mizukami H, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Journal Title: Fukushima Journal of Medical Science Volume: 58 Pages: 136-143
  • DOI: 10.5387/fms.58.136
  • Peer Reviewed
• [Journal Article] 'A single night' beneficial effects of adaptive servo-ventilation on cardiac overload, sympathetic nervous activity, and myocardial damage in patients with chronic heart failure and sleep-disordered breathing (2012)
  • Author(s): Yoshihisa A, Suzuki S, Miyata M, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Journal Title: Circulation Journal Volume: 76 Pages: 2153-2158
  • DOI: 10.1253/circj.CJ-12-0453
  • Peer Reviewed
• [Journal Article] Adaptive servo ventilation improves Cheyne-Stokes respiration, cardiac function, and prognosis in chronic heart failure patients with cardiac resynchronization therapy (2012)
  • Author(s): Miyata M, Yoshihisa A, Suzuki S, Yamada S, Kamioka M, Kamiyama Y, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Journal Title: Journal of Cardiology Volume: 60 Pages: 222-227
  • DOI: 10.1016/j.jjcc.2012.01.021
  • Peer Reviewed
• [Journal Article] Dilated phase of hypertrophic cardiomyopathy caused by two different sarcomere mutations, treated with surgical left ventricular reconstruction and cardiac resynchronization therapy with a defibrillator (2012)
  • Author(s): Sato A, Sakamoto N, Ando K, Kaneshiro T, Uekita H, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Sato M, Tamagawa K, Arimura T, Kimura A, Takeishi Y
  • Journal Title: Internal Medicine Volume: 51 Pages: 2559-6254
  • DOI: 10.2169/internalmedicine.51.7684
  • Peer Reviewed
• [Journal Article] High sensitivity C-reactive protein predicts nonresponders and cardiac deaths in severe heart failure patients after CRT implantation (2012)
  • Author(s): Kamioka M, Suzuki H, Yamada S, Kamiyama Y, Saitoh S, Takeishi Y
  • Journal Title: International Heart Journal Volume: 53 Pages: 306-312
  • DOI: 10.1536/ihj.53.306
  • Peer Reviewed
• [Journal Article] Importance of multi-detector computed tomography for percutaneous coronary intervention in a patient with type V dual left anterior descending artery (2012)
  • Author(s): Yokokawa T, Watanabe K, Sakamoto T, Ohwada T, Takeishi Y
  • Journal Title: Journal of Cardiology Cases Volume: 6 Pages: e100–e102
  • DOI: 10.1016/j.jccase.2012.06.010
  • Peer Reviewed
• [Journal Article] Inducibility of atrial fibrillation caused by acute increase of atrial pressure in rat diseased heart with chronic atrial dilation (2012)
  • Author(s): Suzuki H, Takeishi Y
  • Journal Title: International Heart Journal Volume: 53 Pages: 257-260
  • DOI: 10.1536/ihj.53.257
  • Peer Reviewed
• [Journal Article] Intrathoracic impedance changes reflect reverse left ventricular remodeling in response to cardiac resynchronization therapy in chronic heart failure patients (2012)
  • Author(s): Kaneshiro T, Suzuki H, Yamada S, Kamiyama Y, Saitoh S, Takeishi Y
  • Journal Title: International Heart Journal Volume: 53 Pages: 249-252
  • DOI: 10.1536/ihj.53.249
  • Peer Reviewed
• [Journal Article] Nicorandil prevents Gαq-induced progressive heart failure and ventricular arrhythmias in transgenic mice (2012)
  • Author(s): Hirose M, Takeishi Y, Nakada T, Shimojo H, Kashihara T, Nishio A, Suzuki S, Mende U, Matsumoto K, Matsushita N, Taira E, Sato F, Yamada M
  • Journal Title: PLoS One Volume: 7 Pages: e52667
  • DOI: 10.1371/journal.pone.0052667
  • Peer Reviewed
• [Journal Article] Ongoing myocardial damage in patients with heart failure and preserved ejection fraction (2012)
  • Author(s): Kutsuzawa D, Arimoto T, Watanabe T, Shishido T, Miyamoto T, Miyashita T, Takahashi H, Niizeki T, Takeishi Y, Kubota I
  • Journal Title: Journal of Cardiology Volume: 60 Pages: 454-461
  • DOI: 10.1016/j.jjcc.2012.06.006
  • Peer Reviewed
• [Journal Article] Soluble amyloid precursor protein 770 is released from inflamed endothelial cells and activated platelets: a novel biomarker for acute coronary syndrome (2012)
  • Author(s): Kitazume S, Yoshihisa A, Yamaki T, Oikawa M, Tachida Y, Ogawa K, Imamaki R, Hagiwara Y, Kinoshita N, Takeishi Y, Furukawa K, Tomita N, Arai H, Iwata N, Saido T, Yamamoto N, Taniguchi N
  • Journal Title: Journal of Biological Chemistry Volume: 287 Pages: 40817-40825
  • DOI: 10.1074/jbc.M112.398578
  • Peer Reviewed
• [Journal Article] Uric acid increases the incidence of ventricular arrhythmia in patients with left ventricular hypertrophy (2012)
  • Author(s): Yamada S, Suzuki H, Kamioka M, Kamiyama Y, Saitoh S, Takeishi Y
  • Journal Title: Fukushima Journal of Medical Science Volume: 58 Pages: 101-106
  • DOI: 10.5387/fms.58.101
  • Peer Reviewed
• [Presentation] Overexpressed phoshodiesterase 3A1 protects the heart against angiotensin II-induced cardiac injury via regulating interaction between β-adrenergic and angiotensin II signaling pathways (2012)
  • Author(s): Oikawa M, Iwaya S, Yan C, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] High serum level of tenascin-C is related to coronary plaque rupture in patients with acute coronary syndrome (2012)
  • Author(s): Sakamoto N, Misaka T, Mizukami H, Suzuki S, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Plasma carnitine level in heart failure patients with sleep disordered breathing (2012)
  • Author(s): Miyata M, Yoshihisa A, Yamaki T, Iwaya S, Owada T, Suzuki S, Oikawa M, Sugimoto K, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Soluble amyloid precursor protein 770 is a novel marker for diagnosis of acute coronary syndrome (2012)
  • Author(s): Yamaki T, Yoshihisa A, Miyata M, Suzuki S, Oikawa M, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Kitazume S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Adaptive servo ventilation improves long-term prognosis in heart failure patients with preserved left ventricular ejection fraction and sleep disordered breathing (2012)
  • Author(s): Yoshihisa A, Miyata M, Suzuki S, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Serum cholinesterase level is an important prognostic factor in chronic heart failure (2012)
  • Author(s): Sato T, Yamauchi H, Nakamura Y, Yoshihisa A, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Overnight beneficial impacts of adaptive servo ventilation on cardiac overload, sympathetic nervous activity, and myocardial damage in chronic heart failure patients with Cheyne-Stokes respiration (2012)
  • Author(s): Iwaya S, Yoshihisa A, Miyata M, Suzuki S, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Utility of cardio-ankle vascular index and flow-mediated dilatation for non-invasive detection of vascular dysfunction in sleep disordered breathing (2012)
  • Author(s): Owada T, Yoshihisa A, Iwaya S, Miyata M, Suzuki S, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Adaptive servo ventilation improves cardio-renal function and prognosis in heart failure patients with chronic kidney disease and sleep disordered breathing (2012)
  • Author(s): Owada T, Yoshihisa A, Iwaya S, Miyata M, Suzuki S, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Effect of adaptive servo ventilation on autonomic nervous balance: analysis of heart rate variavility by wireless Holter ECG (2012)
  • Author(s): Iwaya S, Yoshihisa A, Owada T, Miyata M, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] Coronary artery spasm related to thiol oxidation and RhoA activation in aging model with senescence marker protein-30 (smp 30) deficiency (2012)
  • Author(s): Hoshino Y, Saitoh S, Machii H, Yamada S, Misaka T, Miyata M, Mizukami H, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] The impact of the great east Japan earthquake on acute myocardial infarction in Fukushima prefecture (2012)
  • Author(s): Yamaki T, Nakazato K, Kijima M, Maruyama Y, Takeishi Y, Investigators T
  • Organizer: Scientific Sessions of American Heart Association 2012
  • Place of Presentation: Los Angeles, California, USA
  • Year and Date: 20121103-20121107
• [Presentation] The enormous earthquake hit Japan on March 11 increased acute heart failure -analysis of remote monitoring of intrathoracic impedance- (2012)
  • Author(s): Suzuki H, Yamada S, Kamioka M, Kamiyama Y, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] A single night use of adaptive servo ventilation improves renal function in heart failure patients with sleep disordered breathing (2012)
  • Author(s): Suzuki S, Yoshihisa A, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Adaptive servo ventilation improves cardiac function and reduces re-hospitalization in chronic heart failure patients with Cheyne-Stokes respiration after cardiac resynchronization therapy (2012)
  • Author(s): Miyata M, Yoshihisa A, Suzuki S, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Adaptive servo ventilation improves cardio-renal function and prognosis in heart failure patients with chronic kidney disease and sleep disordered breathing (2012)
  • Author(s): Owada T, Yoshihisa A, Miyata M, Suzuki S, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] The association between sleep-disordered breathing and life-threatening ventricular arrhythmias in patients with chronic heart failure (2012)
  • Author(s): Yamada S, Suzuki H, Sato M, Iwaya S, Kamioka M, Kamiyama Y, Suzuki S, Yoshihisa A, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Cardiac overexpression of senescence marker protein 30 inhibits angiotensin II-induced cardiac hypertrophy and remodeling (2012)
  • Author(s): Misaka T, Suzuki S, Miyata M, Kobayashi A, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Anemia has significant impacts for adaptive servo ventilation therapy on heart failure patients with Cheyne-Stokes respiration (2012)
  • Author(s): Suzuki S, Yoshihisa A, Miyata M, Sugimoto K, Yamaki T, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Molecular mechanism of tissue factor regulation through RAGE-MT1-MMP axis in HMGB-1 stimulated-endothelial cells (2012)
  • Author(s): Sugimoto K, Ishibashi T, Takuwa Y, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Adaptive servo ventilation improves long-term prognosis in heart failure patients with preserved left ventricular ejection fraction and sleep disordered breathing (2012)
  • Author(s): Suzuki S, Yoshihisa A, Miyata M, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] T-wave alternans is helpful for predicting recurrence of fatal arrhythmias in ventricular fibrillation survivors (2012)
  • Author(s): Yamada S, Suzuki H, Sato M, Iwaya S, Kamioka M, Kamiyama Y, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Olmesartan inhibits ventricular remodeling and arrhythmias in a mouse model of chronic heart failure (2012)
  • Author(s): Matsushita N, Hirose M, Takeishi Y, Shimojo H, Kashihara T, Nakada T, Taira E, Mende U, Yamada M
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829
• [Presentation] Overnight beneficial impacts of adaptive servo ventilation on cardiac overload, sympathetic nervous activity, and myocardial damage in chronic heart failure patients with Cheyne-Stokes respiration (2012)
  • Author(s): Suzuki S, Yoshihisa A, Miyata M, Sugimoto K, Kunii H, Yamaki T, Nakazato K, Suzuki H, Saitoh S, Takeishi Y
  • Organizer: Congress of the European Society of Cardiology 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 20120825-20120829