Investigation of the treatment of silent heart failure by controllingof multi-organ network and epigenic modulation

• Project/Area Number: 23790830
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamagata University
• Principal Investigator: SHISHIDO Tetsuro 山形大学, 医学部, 助教 (60400545)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 慢性心不全 / 慢性腎臓病 / エピジェネティックス / 臓器障害 / ミッドカイン / AKT / RSK

Research Abstract

Midkine is a heparin-binding growth factor having various functions such as cell growth,cell survival, and migration of inflammatory cells. We have previously reported thatserum midkine levels are independently associated with adverse cardiac events in patientswith heart failure. The aim of this study was to examine the role of midkine on thepathogenesis of the heart failure.
Midkine expression levels were mainly increased after transverse aortic constriction (TAC)surgery. We generated transgenic mice with cardiac specific overexpression of midkine(MK-Tg) using α-myosin heavy chain promoter. After TAC operation, phosphorylation ofextracellular signal-regulated kinase (ERK) 1/2 and AKT, and the expression levels of fetalgene in the heart were significantly increased in MK-Tg mice than in WT mice. The ratioof left ventricular weight to body weight and left ventricular end-diastolic dimension weresignificantly increased, and fractional shortening and maximum and minimum of leftventricular developed pressure were significantly decreased in MK-Tg mice than in WTmice after TAC operation. The degree of interstitial fibrosis and profibrotic geneexpressions were significantly higher in MK-Tg mice than in WT mice. Consistent withthese results, Kaplan-Meier analysis revealed that the survival rate in MK-Tg mice wassignificantly lower compared with WT mice. We concluded that cardiac overexpression ofMK plays a critical role in pressure overload induced cardiac hypertrophy and remodeling.

Research Products

• [Journal Article] Long PentraxinPTX3 Exacerbates PressureOverload-Induced Left VentricularDysfunction (2013)
  • Author(s): Suzuki S, Shishido T, Funayama A, Netsu S,Ishino M, Kitahara T, Sasaki T, Katoh S,Otaki Y, Watanabe T, Shibata Y, MantovaniA, Takeishi Y, Kubota I
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Renal tubulointerstitial damage is associatedwith short-term cardiovascular events inpatients with myocardial infarction (2013)
  • Author(s): Funayama A, Shishido T, Miyashita T,Netsu S, Otaki Y, Arimoto T, Takahashi H,Miyamoto T, Watanabe T, Konta T, Kubota I
  • Journal Title: Circ J Volume: 77 Pages: 484-9
  • Peer Reviewed
• [Journal Article] Long pentraxin PTX3 exacerbates pressure overload-induced left ventricular dysfunction. (2013)
  • Author(s): Suzuki S et al.
  • Journal Title: PLOS ONE Volume: 8 Issue: 1 Pages: e53133-e53133
  • DOI: 10.1371/journal.pone.0053133
  • Peer Reviewed
• [Journal Article] Renal Tubulointerstitial Damage Is Associated With Short-Term Cardiovascular Events in Patients With Myocardial Infarction (2013)
  • Author(s): Funayama A, Shishido T, Miyashita T, Netsu S, Otaki Y, Arimoto T, Takahashi H, Miyamoto T, Watanabe T, Konta T, Kubota I.
  • Journal Title: Circulation Journal Volume: 77 Issue: 2 Pages: 484-489
  • DOI: 10.1253/circj.CJ-12-0640
  • NAID: 10031138929
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Impact ofinsulin resistance on silent and ongoingmyocardial damage in normal subjects: theTakahata study (2012)
  • Author(s): Narumi T, Shishido T, Kiribayashi N,Kadowaki S, Nishiyama S, Takahashi H,Arimoto T, Miyashita T, Miyamoto T,Watanabe T, Shibata Y, Konta T, Ueno Y,Kato T, Kayama T, Kubota I
  • Journal Title: Exp Diabetes Res Volume: 2012 Pages: 815098-815098
  • Peer Reviewed
• [Journal Article] p90RSK targetsthe ERK5-CHIP ubiquitin E3 ligase activityin diabetic hearts and promotes cardiacapoptosis and dysfunction (2012)
  • Author(s): Le NT, Takei Y, Shishido T, Woo CH,Chang E, Heo KS, Lee H, Lu Y, Morrell C,Oikawa M, McClain C, Wang X, Tournier C,Molina CA, Taunton J, Yan C, Fujiwara K,Patterson C, Yang J, Abe J
  • Journal Title: Circ Res Volume: 110 Pages: 536-50
  • Peer Reviewed
• [Journal Article] Impact of insulin resistance on silent and ongoing myocardial damage in normal subjects: the Takahata study. (2012)
  • Author(s): Narumi T, Shishido T, Kiribayashi N, Kadowaki S, Nishiyama S, Takahashi H, Arimoto T, Miyashita T, Miyamoto T, Watanabe T, Shibata Y, Konta T, Ueno Y, Kato T, Kayama T, Kubota I.
  • Journal Title: Diabetes Res. Volume: 2012 Pages: 815098-815098
  • DOI: 10.1155/2012/815098
  • Peer Reviewed
• [Journal Article] p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. (2012)
  • Author(s): Le NT, Takei Y, Shishido T*, Woo CH, Chang E, Heo KS, Lee H, Lu Y, Morrell C, Oikawa M, McClain C, Wang X, Tournier C, Molina CA, Taunton J, Yan C, Fujiwara K, Patterson C, Yang J, Abe J.
  • Journal Title: Circ Res. Volume: 17 Issue: 4 Pages: 536-550
  • DOI: 10.1161/circresaha.111.254730
  • Peer Reviewed
• [Journal Article] Serum pregnancy-associated plasmaprotein a in patients with heart failure (2011)
  • Author(s): Funayama A, Shishido T, Netsu S, Ishino M,Sasaki T, Katoh S, Takahashi H, Arimoto T,Miyamoto T, Nitobe J, Watanabe T, Kubota I
  • Journal Title: J Card Fail Volume: 17 Pages: 819-26
  • Peer Reviewed
• [Journal Article] 8-Hydroxy-2'-deoxyguanosineis a prognostic mediator for cardiac event (2011)
  • Author(s): Suzuki S, Shishido T, Ishino M, Katoh S,Sasaki T, Nishiyama S, Miyashita T,Miyamoto T, Nitobe J, Watanabe T, TakeishiY, Kubota I
  • Journal Title: Eur J Clin Invest Volume: 41 Pages: 759-66
  • Peer Reviewed
• [Journal Article] Differential regulation of diacylglycerol kinase isoform in human failing hearts. (2011)
  • Author(s): Bilim O, Shishido T, Toyama S, Suzuki S, Sasaki T, Kitahara T, Sadahiro M, Takeishi Y, Kubota I.
  • Journal Title: J Cardiothorac Surg. Volume: 6 Issue: 1 Pages: 65-65
  • DOI: 10.1186/1749-8090-6-65
  • Peer Reviewed
• [Journal Article] Serum pregnancy-associated plasma protein a in patients with heart failure (2011)
  • Author(s): Akira Funayama
  • Journal Title: J Card Fail Volume: 17 Issue: 10 Pages: 819-819
  • DOI: 10.1016/j.cardfail.2011.05.011
  • Peer Reviewed
• [Presentation] Cardiac-specificoverexpression of high-mobility group box1 protects cardiomyocyte from apoptosisduring the pathogenesis of doxorubicincardiomyopathy (2012)
  • Author(s): Narumi T, Shishido T, Kadowaki S,Funayama A, Otaki Y, Honda Y, Sasaki S,Hasegawa H, Nishiyama S, Takahashi H,Arimoto T, Miyashita T, Miyamoto T,Watanabe T, Kubota I
  • Organizer: American HeartAssociation Scientific Sessions 2012, Los Angeles, America
  • Place of Presentation: Los Angeles Convention Center
  • Year and Date: 2012-11-03
• [Presentation] Thelong pentraxin PTX3 exacerbates pressureoverload-induced left ventriculardysfunction (2012)
  • Author(s): Suzuki S, Shishido T, Sasaki T, Ishino M,Kubota I, Mantovani A, Takeishi Y
  • Organizer: European Society of Cardiology 2012 World Congress, Munich
  • Place of Presentation: Munich Messe, Germany
  • Year and Date: 2012-08-25
• [Presentation] Overexpression of midkineaggravates cardiac dysfunction and adversemyocardial remodeling induced by pressureoverload (2012)
  • Author(s): Netsu S, Shishido T, Ishino M, Funayama A,Kadowaki S, Narumi T, Ohtaki Y,Hasegawa H, Honda S, Tamura H,Nishiyama S, Arimoto T, Takahashi H,Miyashita T, Miyamoto T, Watanabe T,Kubota I
  • Organizer: The 76th Annual ScientificMeeting of the Japanese Circulation Society,Fukuoka
  • Place of Presentation: FukuokaConvention Center
  • Year and Date: 2012-03-16
• [Presentation] Cardiac-specific overexpression of highmobility group box 1 (HMGB1) preventscardiac dysfunction induced by pressureoverload (2012)
  • Author(s): Funayama A, Shishido T, Ishino M, OhtakiY, Netsu S, Hasegawa H, Honda S,Kadowaki S, Narumi T, Nishiyama S,Arimoto T, Takiahashi H, Miyashita T,Miyamoto T, Watanabe T, Kubota I
  • Organizer: The 76th Annual ScientificMeeting of the Japanese Circulation Society,Fukuoka
  • Place of Presentation: FukuokaConvention Center
  • Year and Date: 2012-03-16
• [Presentation] The long pentraxin PTX3 exacerbates pressure overload-induced left ventricular dysfunction. (2012)
  • Author(s): Suzuki S, Shishido T, Sasaki T, Ishino M, Kubota I, Mantovani A, Takeishi Y
  • Organizer: European Society of Cardiology 2012 World Congress
  • Place of Presentation: ﾐｭﾝﾍﾝﾒｯｾ (ﾐｭﾝﾍﾝ､ﾄﾞｲﾂ)
• [Presentation] Cardiac-specific overexpression of high-mobility group box 1 protects cardiomyocyte from apoptosis during the pathogenesis of doxorubicin cardiomyopathy. (2012)
  • Author(s): Narumi T, Shishido T, Kadowaki S, Funayama A, Otaki Y, Honda Y, Sasaki S, Hasegawa H, Nishiyama S, Takahashi H, Arimoto T, Miyashita T, Miyamoto T, Watanabe T, Kubota I
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: ﾛｻﾝｾﾞﾙｽｺﾝﾍﾞﾝｼｮﾝｾﾝﾀｰ (ｶﾘﾌｫﾙﾆｱ､ｱﾒﾘｶ)
• [Presentation] Multiple kidney biomarkers can risk-stratify chronic heart failure patients. (2012)
  • Author(s): Kadowaki S, Shishido T, Narumi T, Otaki Y, Honda S, Hasegawa H, Funayama A, Arimoto T, Takahashi H, Miyamoto T, Watanabe T, Kubota I
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: ﾛｻﾝｾﾞﾙｽｺﾝﾍﾞﾝｼｮﾝｾﾝﾀｰ (ｶﾘﾌｫﾙﾆｱ､ｱﾒﾘｶ)
• [Presentation] Combination of iodine-123-metaiodobenzylguanidine imaging and heart-type fatty acid binding protein for risk stratification in heart failure with preserved ejection fraction. (2012)
  • Author(s): Katoh S, Shishido T, Arimoto T, Watanabe T, Kubota I
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: ﾛｻﾝｾﾞﾙｽｺﾝﾍﾞﾝｼｮﾝｾﾝﾀｰ (ｶﾘﾌｫﾙﾆｱ､ｱﾒﾘｶ)
• [Presentation] Overexpression of Midkine Aggravates Cardiac Dysfunction and Adverse Myocardial Remodeling Induced by Pressure Overload (2012)
  • Author(s): Netsu S
  • Organizer: 日本循環器学会
  • Place of Presentation: 福岡市 福岡国際会議場
• [Presentation] Cardiac-specificoverexpression of high mobility group box1 (HMGB1) attenuates cardiac dysfunctioninduced by pressure overload (2011)
  • Author(s): Funayama A, Shishido T, Netsu S, Ishino M,Otaki Y, Honda S, Hasegawa H, KadowakiS, Narumi T, Nishiyama S, Takahashi H,Arimoto T, Miyashita T, Miyamoto T,Watanabe T, Woo CH, Kuwahara K, NakaoK, Takeishi Y, Kubota I
  • Organizer: AmericanHeart Association Scientific Sessions 2011,Orlando, America
  • Place of Presentation: Orange County Convention Center
  • Year and Date: 2011-11-14