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1998 Fiscal Year Final Research Report Summary

Analyses of transcriptional regulation and signal transduction of sarcoplasmic reticulum Ca^<2+>

Research Project

Project/Area Number 09670692
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionGunma University School of Medicine

Principal Investigator

ARAI Masashi  Gunma University, Second Department of Internal Medicine, Research Fellow, 医学部, 助手 (60270857)

Project Period (FY) 1997 – 1998
KeywordsSERCA2 / doxorubicin / heart failure / reactive oxygen / Egr-1 / MAPK / gene transcription
Research Abstract

Impaired Ca2+ handling in sarcoplasmic reticulum is a central mechanism that accounts for the cardiac dysfunction seen in doxorubicin induced-cardiomyopathy. We have recently demonstrated that mRNA expression for sarcoplasmic reticulum Ca2+-ATPase (SERCA2), the major Ca2+ transport protein in sarcoplasmic reticulum, is markedly decreased in doxorubicin induced-failing hearts.
The purpose of this study was to clarify the molecular mechanisms by which doxorubicin down-regulates SBRCA2 gene. N-acetylcysteine ; an anti-oxidant, protected SERCA2 mRNA levels from a decrease induced by doxorubicin in cultured rat cardiac myocytes, and the concentration of hydrogen peroxide was 3-fold higher than basal level, suggesting that hydrogen peroxidels an intracellular mediator of doxorubicin. Luciferase reporter assay revealed that 5' flanking sequence from -284 to -72 bp of SERCA2 gene has a doxorubicin responsible element. Of the transcription factors that have putative binding motifs in the 5' flanking -284 to -72 bp region of SERCA2 gene, the expression of Egr-1 mRNA was markedly increased after doxorubicin administration. Over-expression of Egr-1 significantly diminished the transcription of SERCA2 gene. Additionally, antisense oligonucleotides against Egr-1 rescued the doxorubicin induced-decrease of SERCA2 mRNA expression. These results suggest that Egr-1 is a transcriptional inhibitor of SERCA2 gene under doxorubicin administration. Finally, we clarified kinases which controls Egr-1 and, thus SERCA2 genes. Three MAP kinases ; p44/42 MAP kinase, p38 MAP kinase and SAPK/JNK were all activated by doxorubicin. PD98059, a specific blocker of p44/42 MAP kinase kinase, had a preventive effect on the doxorubicin induced-increase of Egr- 1 gene and the decrease of SERCA2 gene.
Our studies indicate that reactive oxygen intermediates, transcription factor Egr-1 and p44/42 MAP kinase have a pivotal role for the transcriptional regulation of SERCA2 gene in doxorubicin signaling pathway.

  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Masashi Arai: "Sarcoplasmle reticulum genes are selectively down-regulated in cardiomyopcthy produced by doxorubicin in rabbits" J Mol Cell Cardiol. 30. 243-254 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tatsuya Iso: "Humoral factor(5) produced by pressure overload enhance cardiac hypertrophy" Am J Physiol (Heart Circ Physiol). 273. H113-H118 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshio Ohyama: "Molecular cloning of rat klotho cDNA : Markedly decreased expression of klotho by acute inflammatory stress" Blochem Biophys Res Commun. 251. 920-925 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tomoyuki Yokoyama: "Tumor necrosis factor-alpha clecreases the phosphorylation levels of phospholamban and tropanin I in spontaneously beating rat neoratal cardiac" myocytes (標題続き) J Mol Cell Cardiol. 31. 261-273 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masahiro Inoue: "Impaired expression of brain nctriuretic peptide gene in deabetic rats with myocardial infarction" Exp Clin Endocrinol Diabetes. 106. 483-487 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsugiyasu Kanda: "Increased sererity of viral myocarditis in mlce lacking lymphocyte maturation" Int J Cardiol. 68. 13-22 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 新井昌史: "医学のあゆみ" 医歯薬出版社, 東京, 6 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 新井昌史: "臨床医" 中外医学社, 東京, 2 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Iso T,Arai M,Wada A,Kogure K,Suzuki T,Nagai R.: "Humoral factor(s) produced by pressure overload enhance cardiac hypertrophy and natriuretic peptide expression." Am J Physiol(Heart Circ Physiol). 273. H113-H118 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Arai M,Tomaru K,Takizawa T,Sekiguchi K,Yokoyama T,Suzuki T,Nagai R.: "Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits" J Mol Cell Cardiol. 30. 243-254 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ohyama Y,Kurabayashi M,Masuda H,Nakamura T,Aihara Y,Kaname T,Arai M,Aizawa H,Matsumura Y,Kuro-o M,Nabeshima Y,Nagai R.: "Molecular cloning of rat klotho cDNA : Markedly decreased expression of klotho by acute inflammatory stress" Biochem Biophys Res Commun. 251. 920-825 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yokoyama T,Arai M,Sekiguchi, K,Tanaka T,Kanda T,Suzuki T,Nagai R.: "Tumor necrosis factor-alpha decreases the phosphorylation levels of phospholamban and troponin I in spontaneously beating rat neonatal cadiac myocytes" J Moll Cell Cardiol. 31. 261-273 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inoue M,Kanda T,Arai M,McManus BM,Suzuki T,Kobayashi I,Nagai R.: "Impaired expression of atrial natriuretic peptide in diabetic rats with myocardial infarction" Res Commun Mol Pathol Pharmacol. 100. 327-338 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inoue M,Kanda T,Arai M,Suga T,Suzuki T,Kobayashi I,Nagai R.: "Impaired expression of brain natriuretic peptide gene in diabetic rats with myocardial infarction" Exp Clin Endocrinol Diabetes. 106. 483-487 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kanda T,Koike H,Arai M,Wilson JE,Carthy CM,Yang D,McManus BM,Nagai R,Kobayashi I.: "Increased severity of viral myocarditis in mice lacking lymphocyte maturation" Int J Cardiol. 68. 13-22 (1999)

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

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Published: 1999-12-08  

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