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

2012 Fiscal Year Final Research Report

• 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
• Keywords: 慢性心不全 / 慢性腎臓病 / エピジェネティックス

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 Pages: e53133
  • 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] 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
  • 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] 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
• [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] 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