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1995 Fiscal Year Final Research Report Summary

Roles of cell cycle regulators in the mechanism of cardiac hypertrophy

Research Project

Project/Area Number 06670699
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionTokyo Medical and Dental University

Principal Investigator

ITO Hiroshi  The 2nd Department of Medicine Tokyo Medical and Dental University Assistant Professor, 医学部, 助手 (10232464)

Co-Investigator(Kenkyū-buntansha) HIROE Michiaki  The 2nd Department of Medicine Tokyo Medical and Dental University Lecturer, 医学部, 講師 (80101872)
Project Period (FY) 1994 – 1995
KeywordsHypertrophy / Cardiomyocytes / Cell cycle / P21 / P16 / Cyclines / Retinoblastoma Tumor Suppresser
Research Abstract

Cell cycle inhibitors, p21^<cip1> and p16^<INK4> mediate growth arrest by inhibiting the action of G1 cyclin-dependent kinases (cdks). We produced adenovirus vectors containing coding sequences of the p21^<cip1> (Ax1CAp21) and p16^<INK4> gene (Ax1CAp16), and investigated wether gene transfer of p21^<cip1> and p16^<INK4> inhibit serum-induced hypertrophy of neonatal rat cardiomyocytes in vitro. Northern blot analysis revealed that endogenous p21 mRNA was up-regulated by the stimulation with 10% fetal calf serum (FCS), but p16 mRNA was not in cardiomyocytes. Ax1CAp21 (50 pfu per cell) and Ax1CAp16 (50 pfu per cell) caused significant inhibition of muscle specific gene, (genetic markers of cardiomyocyte hypertrophy), expressions induced by 10% FCS.Ax1CAp21 and Ax1CAp16 also inhibited serum-induced increases of cell surface area, as well as [^3H] leucine incorporation. However, the number of BrdU-positive myocyte was less than 5% of total myocytes whether of not treated with FCS,and did not alter by infection with Ax1CAp21 or Ax1CAp16. Further, antisense oligonucleotides against cyclin D1, one of major G1 cyclins, as well as overexpression of unphosphorylated retinoblastoma tumor suppresser gene (Rb) product overexpressed by adenovirus vector inhibited serum-induced cardiomyocyte hypertrophy. The results of our present study indicate that G1 cdk inhibitors inhibit hypertrophy of cardiomyocytes, and that the cdk4-cyclin D1 complex and its target protein Rb may, at least, mediate their inhibitory action.

  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Tamamori M,Ito H,et al.: "Endothelin-3 Induces Hypertrophy of Cardiomyocytes by The Endogenous Endothelin-1-Mediated Mechanism." J.Clin.Invest.97. 366-372 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akimoto H,Ito H,Tanaka M,et al.: "Heparin and Heparan Sulfate Block Angiotensin II-induced Hypertrophy in Cultured Neonatal Rat Cardiomyocytes:A Possible Role of Intrinsic Heparin-like Molecules in Regulation of Cardiomyocyte Hypertrophy." Circulation.93. 810-816 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fujisaki H,Ito H. Hirata Y,et al.: "Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression." J.Clin.Invest.96. 1059-1065 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka M,Ito H,Adachi S,et al.: "Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in culutred neonatal rat cardiomyhocytes." Circ.Res.75. 426-433 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ito H,Hiroe M,Hirata Y,et al.: "Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload." Circulation.89. 2198-2203 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Adachi S,Uchida S,Ito H,et al.: "Two isoforms of chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts." J.Biol.Chem.269. 17677-17683 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ito H.: "Endothelin and cardiac hypertrophy.in Endotelial modulation of cardiac function.ed.Lewis,M.J.and Dhah,A." Harwood Academic Publishers.London,(in press), (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 伊藤宏 他: "心不全と一酸化窒素 「心不全治療」矢崎義雄 監修" メディカルレビュー社(in press), (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tamamori M,Ito H,Adachi S,Akimoto H,Marumo F,and Hiroe M: "Endothelin-3 Induces Hypertrophy of Cardiomyocytes by The Endogenous Endothelin-1 Mediated Mechanism" J.Clin.Invest. 97. 366-372 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Lin M,Ito H,Akimoto H,Tamamori M,Fujisaki H,Adachi S,Marumo F,Hiroe M: "Cicletanine Inhibits Endothelin-1-Induced Hypertrophy of Rat Cardiomyocytes" Pharmacometrics. 51. 1-6 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akimoto H,Ito H,Tanaka M,Adachi S,Tamamori M,Lin M,Fujisaki H,Marumo F,Hiroe M: "Heparin and Heparan Sulfate Block Angiotensin II-induced Hypertrophy in Cultured Neonatal Rat Cardiomyocytes : A Possible Role of Intrinsic Heparin-like Molecules in Regulation of Cardiomyocyte Hypertrophy" Circulation. 93. 810-816 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fujisaki H,Ito H,Hirata Y,Tanaka M,Hata M,Lin M,Adachi S,Akimoto H,Marumo F,and Hiroe M: "Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression" J.Clin.Invest. 96. 1059-1065 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka M,Hiroe M,Ito H,Nishikawa T,Adachi S,Aonuma K,Marumo F: "Differential localization of atrial natriuretic peptide and skeletal alpha-actin messenger RNAs in left ventricular myocytes of patients with dilated cardiomyopathy" J.Am.Coll.Cardiol. 26. 85-92 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsujino M,Hirata Y,Ito H,Kangawa K,Matsuo H,Marumo F: "Interleukin-1b stimulates release of atrial and brain natriuretic peptide via different mechanisms" Biomed.Res. 16. 91-95 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Adachi S,Ito H,Ohta Y,Tanaka M,Ishiyama S,Nagata M,Toyozaki T,Hirata Y,Marumo F,Hiroe M: "Distribution of mRNAs for Natriuretic Peptides in the Right Ventricular Hypertrophy after Pulmonary Artery Banding" Am J Physiol. 268. H162-H169 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka M,Ito H,Adachi S,Akimoto H,Nishikawa T,Kasajima T,Marumo F,Hiroe M: "Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes" Circ.Res. 75. 426-433 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koike A,Hiroe M,Adachi H,Yajima T,Yamauchi, Y,Nogami A,Ito H,Miyahara, Y,Korenaga, M,Marumo F: "Oxygen uptake kinetics are determined by cardiac function at onset of exercise rather than peak exercise in patients with prior myocardial infarction" Circulation. 90. 2324-2332 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ito H,Hiroe M,Hirata Y,Fujisaki H,Adachi S,Akimoto H,Ohta Y,Marumo F: "Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload" Circulation. 89. 2198-2203 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsujino M,Hirata Y,Imai T,Kanno K,Eguchi S,Ito H,Marumo F: "Induction of nitric oxide sythesase gene by interleukin-1b in cultured rat cardiocytes" Circulation. 90. 375-383 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Adachi S,Uchida S,Ito H,Hata M,Hiroe M,Marumo F,Sasaki S: "Two isoforms of chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts" J.Biol.Chem. 269. 17677-17683 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Adachi S,Ito H,Hiroe M,Fujisaki H,Tanaka M,Akimoto H,Marumo F: "Insulin-like growth factor-II induces hypertrophy with increased expression of muscle specific genes in cultured rat cardiomyocytes" J.Mol.Cell.Cardiol. 26. 789-795 (1994)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1997-03-04  

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