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2005 Fiscal Year Final Research Report Summary

The Efficacy of Statin for Coronary Spasm

Research Project

Project/Area Number 16590698
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionKumamoto University

Principal Investigator

NAKAYAMA Masafumi  Kumamoto University, Department of Cardiovascular Medicine, Graduate School of Medical Sciences., 医学部附属病院, 非常勤診療医師 (30346986)

Co-Investigator(Kenkyū-buntansha) OGAWA Hisao  Kumamoto University, Department of Cardiovascular Medicine, Graduate School of Medical Sciences., Professor, 大学院・医学薬学研究部, 教授 (50177135)
Project Period (FY) 2004 – 2005
KeywordsCoronary Spasm / HMG-CoA Reductase Inhibitor / Statin / Endothelial Nitric Oxide Synthase / -786T / C Polymorphism / Transcription / Replication Protein A1 / Reporter Gene Assay
Research Abstract

Background : HMG-CoA reductase inhibitors (statins) increase endothelial nitric oxide (NO) production, although the precise mechanism of this statin induced increase in NO production remains to be elucidated. Previously, we found a -786T/C polymorphism in the 5'-flanking region of the eNOS gene, and showed that the -786C allele significantly reduced the transcriptional activity of the eNOS gene compared with the -786T allele. We also found that the -786T/C polymorphism is strongly associated with coronary spasm and myocardial infarction, especially in patients without coronary organic stenosis. We furthermore discovered that replication protein A1 (RPA1), known as a single-stranded DNA binding protein essential for DNA repair, replication and recombination, functions as a repressor of the transcription activity of the eNOS gene with the -786C allele.
Methods and Results : We examined endothelial nitric oxide synthase (eNOS) mRNA levels, mRNA stability and the transcriptional activities … More of the eNOS gene in human umbilical vein endothelial cells treated with fluvastatin and simvastatin. We further examined whether the effects of these statins differ dependent upon the -786T>C polymorphism in the eNOS gene, and whether these statins affect gene expression of replication protein A1 (RPA1), which is known to reduce the transcriptional activity of the eNOS gene with the -786C allele. Utilizing the real-time reverse transcription-polymerase chain reaction, fluvastatin significantly increased eNOS mRNA levels and mRNA stability, and decreased RPA1 mRNA levels. Luciferase reporter gene assays revealed that fluvastatin significantly increased the transcriptional activity of the eNOS gene. The effect of fluvastatin was stronger in the -786C/C genotype than in the -786T/T genotype. Simvastatin increased eNOS mRNA levels and mRNA stability, but did not affect the transcriptional activity of the eNOS gene. Fluvastatin increased eNOS mRNA levels by enhancing both the transcriptional activity and mRNA stability.
Conclusion : The effect of fluvastatin on the transcriptional activity was augmented in the -786C/C genotype, probably because of a decrease in RPA1 gene expression. Simvastatin increased eNOS mRNA levels only by enhancing mRNA stability. The present study suggests that fluvastatin increases endothelial NO activity and thus may be more beneficial to patients with the -786C allele. Less

  • Research Products

    (29 results)

All 2006 2005 2003 2002 2001 2000 1999 1998 1997 1996 1994 1992 1991 1989 1988

All Journal Article (29 results)

  • [Journal Article] A -786T>C Polymorphism in the Endothelial Nitric Oxide Synthase Gene Reduces Serum Nitrite/Nitrate Levels from the Heart due to an Intracoronary Injection of Acetylcholine2006

    • Author(s)
      Nakayama M, Ogawa H, et al.
    • Journal Title

      Phamacogenetics and Genomics 16

      Pages: 339-345

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Direct Effects of Aldosterone on Cardiomyocytes in the Presence of Normal and Elevated Extracellular Sodium2006

    • Author(s)
      Yamamuro M, Yoshimura M, Nakayama M, Ogawa H, et al.
    • Journal Title

      Endocrinology 147

      Pages: 1314-1321

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease2006

    • Author(s)
      Koga H, Ogawa H, et al.
    • Journal Title

      European heart journal. 27

      Pages: 817-823

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Low-grade inflammation,thrombogenicity,and atherogenic lipid profile in cigarette smokers.2006

    • Author(s)
      Yasue H, Ogawa H, et al.
    • Journal Title

      Circulation Journal 70

      Pages: 8-13

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Increase in the Transcriptional Activity of the Endothelial Nitric Oxide Synth ase Gene With Fluvastatin : A Relation With the -786T>C Polymorphism2005

    • Author(s)
      Abe K, Nakayama M, Ogawa H, et al.
    • Journal Title

      Phamacogenetics and Genomics 15

      Pages: 329-336

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Id1 gene transfer confers angiogenic property on fully differentiated endothelial cells and contributes to therapeutic angiogenesis2005

    • Author(s)
      Nishiyama K, Ogawa H, et al.
    • Journal Title

      Circulation 112

      Pages: 2840-2850

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mechanism of plaque stabilization with statins.2003

    • Author(s)
      Libby P, Aikawa M.
    • Journal Title

      Am J Cardiol. 91(suppl)

      Pages: 4B-8B

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Endothelium-dependent effects of statins.2003

    • Author(s)
      Wolfrum S, Jensen KS, Liao JK.
    • Journal Title

      Arterioscler Thromb Vasc Biol. 23

      Pages: 729-736

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] HMG-CoA reductase inhibitor increases GTP Cyclohydrolase I mRNA and tetrahydrobiopterin in vascular in endothelial cells.2003

    • Author(s)
      Hattori Y, Nakanishi N, Akinoto K, et al.
    • Journal Title

      Arterioscler Thromb Vasc Biol. 23

      Pages: 176-182

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The T-786C endotheial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study.2003

    • Author(s)
      Rossi GP, Cesari M, Zanchetta M, et al.
    • Journal Title

      J Am Coil Cardiol 41

      Pages: 930-937

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.2002

    • Author(s)
      Sukhova GK, Williams JK, Libby P.
    • Journal Title

      Arterioscler Thromb Vasc Biol. 22

      Pages: 1452-1458

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of aherosclerosis in cholesterol-fed rabbits.2001

    • Author(s)
      Rikitake Y, Kawashima S, Takeshita S, et al.
    • Journal Title

      Athrosclerosis. 105

      Pages: 87-96

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] T^<-786>→C mutation in the 5' flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis.2000

    • Author(s)
      Nakayama M, Yasue H, Yoshimura M, et al.
    • Journal Title

      Am J Cardiol. 86

      Pages: 628-634

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T→C mutation associated with coronary spastic angina.2000

    • Author(s)
      Miyamoto Y, Saito Y, Nakayama M, et al.
    • Journal Title

      Hum Mol Genet. 9

      Pages: 2629-2637

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury.2000

    • Author(s)
      Indolfi C, Cioppa A, Stabile E, et al.
    • Journal Title

      J Am Coil Cardiol 35

      Pages: 214-221

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The HMG CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.2000

    • Author(s)
      Kureishi Y, Luo Z, Shiojima I, et al.
    • Journal Title

      Nat Med. 6

      Pages: 1004-1010

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] T^<-786>→C mutation in the 5' flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm.1999

    • Author(s)
      Nakayama M, Yasue H, Yoshimura M, et al.
    • Journal Title

      Circulation. 99

      Pages: 2864-2870

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] New insights into the phamacodymnamic and pharmacokinetic properties of statins.1999

    • Author(s)
      Corsini A, Bellosta S, Baetta R, et al.
    • Journal Title

      Pharmacol Ther. 84

      Pages: 413-428

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.1998

    • Author(s)
      Laufs U, Fata VL, Plutzky J, et al.
    • Journal Title

      Circulation. 97

      Pages: 1129-1135

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelia-1 and endothelial nitric oxide synthase in vascular endothelial cells.1998

    • Author(s)
      Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al.
    • Journal Title

      J Clin Invest. 101

      Pages: 2711-2719

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Structure of the single-stranded-DNA-binding domain of replication protein A bound to DNA.1997

    • Author(s)
      Bochkarev A, Pfuetzner RA, Edwards AM, et al.
    • Journal Title

      Nature. 385

      Pages: 176-181

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month.1997

    • Author(s)
      O'Driscoll G, Green D, Taylor RR.
    • Journal Title

      Circulation. 95

      Pages: 1126-1131

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina.1996

    • Author(s)
      Kugiyama K, Yasue H, Okumura K, et al.
    • Journal Title

      Circulation. 94

      Pages: 266-272

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.1994

    • Author(s)
      Ziche M, Morbidelii L, Masini E, et al.
    • Journal Title

      J Clin Invest. 94

      Pages: 2036-2044

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Platelet-derived growth factor suppresses and fibroblast growth factor enhances cytokine-induced production of nitric oxide by cultured smooth muscle cells. Effects on cell proliferation.1992

    • Author(s)
      Scott-Burden T, Schini VB, Elizondo E, et al.
    • Journal Title

      Circ Res. 71

      Pages: 1088-1100

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nitric oxide : physiology, pathophysiolagy, and pharmacology.1991

    • Author(s)
      Moncada S, Palmer RM, Higgs EA.
    • Journal Title

      Phamacol Rev. 43

      Pages: 109-142

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nitric oxide : an endogenous modulator of leukocyte adhesion.1991

    • Author(s)
      Kubes P, Suzuki M, Granger DN.
    • Journal Title

      Proc Natl Acad Sci U S A. 88

      Pages: 4651-4655

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nitric oxide-generating vasodilatators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.1989

    • Author(s)
      Garg UC, Hassid A.
    • Journal Title

      J Clin Invest. 83

      Pages: 1774-1777

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Purification and characterization of replication protein A, a cellular protein required for in vitro replication of simian virus 40 DNA.1988

    • Author(s)
      Wold MS, Kelly T.
    • Journal Title

      Proc Natl Acad Sci USA. 85

      Pages: 2523-2527

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

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Published: 2007-12-13  

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