2000 Fiscal Year Annual Research Report

遺伝子転写からみた心不全発症機構の解明と治療への応用

Research Project

Project/Area Number	11838001
Research Institution	Gunma University School of Medicine
Principal Investigator	新井昌史群馬大学, 医学部, 講師 (60270857)
Co-Investigator(Kenkyū-buntansha)	永井良三東京大学, 医学部, 教授 (60207975) 倉林正彦群馬大学, 医学部, 教授 (00215047)
Keywords	心筋小胞体 / SERCA2 / ドキソルビシン / 遺伝子転写 / Egr-1 / ERK / 圧負荷 / Sp1
Research Abstract	心筋小胞体Ca2+-ATPase遺伝子(SERCA2)mRNA発現は、心不全で低下し、心収縮力低下をもたらす重要な機序になる。我々は、心筋毒性の強い抗癌剤であるドキソルビシンを用いて培養心筋細胞で心不全モデルを作り、SERCA2遺伝子発現の低下に至る機序を検討した。ドキソルビシン投与下では、SERCA2遺伝子の転写活性が低下しており、mRNA発現の低下はSERCA2遺伝子の転写活性の低下に由来した。ドキソルビシンに最も感受性の高い領域はGC配列に富む近位部(-284〜-72bp)であった。この領域には、複数のSp1、Egr-1、AP2転写因子結合部位が存在する。ドキソルビシン投与下ではEgr-1mRNAの発現量が著増しており、Egr-1はSERCA2遺伝子の転写を抑制することが判明した。従って、ドキソルビシンの作用はEgr-1を介してSERCA2遺伝子に伝えられると考えられる。実際に、Egr-1のSERCA2遺伝子への結合がドキソルビシン投与群では増加していることや、Egr-1のアンチセンスオリゴヌクレオチドの導入によってドキソルビシンの効果が減弱するなどが確認された。さらに、Egr-1転写因子を誘導する細胞内情報伝達系はERKであることを明らかにした。一方、高血圧などの圧負荷により、心臓は肥大から心不全に至る。この時、SERCA 2mRNA発現が低下するが、これはSERCA2遺伝子5'転写調節領域近位部のGC-Box中の上流側から1番目と6番目のSp1結合部位が転写活性の抑制に寄与していることを、in vivo gene transfer法によって明らかにした。以上、心不全でのSERCA2 mRNA発現の低下は、単にmRNAの非特異的な障害によってもたらされるのではなく、特定の転写因子がSERCA2遺伝子の特定部位に結合して引き起こされる制御された過程である事を明らかにした。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Arai M: "Mechanism of doxorubicin induced inhibition of sarcoplasmic reticulum Ca2+-ATPase gene transcription."Circ Res. 86. 8-14 (2000)
[Publications] Arai M: "Function and regulation of sarcoplasmic reticulum Ca2+-ATPase.Advances during the past decade and prospects for the coming decade."Jpn Heart J. 41. 1-13 (2000)
[Publications] Seta Y: "Interleukin-18 in patients with congestive heart failure : Induction of atrial natriuretic peptide gene rxpression"Molecular Pathology and Pharmacology. (in press). (2000)
[Publications] Seta Y: "Interleukin-18 in acute myocardial infarction"Heart. 84. 668-669 (2000)
[Publications] Aihara Y: "Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy.Role of M-CAT element within the promoter"Hypertension. 35. 48-53 (2000)
[Publications] Oishi Y: "Unclassified connective tissue disease presenting as cardiac tamponade -A case report-"Jpn Circ J. 64. 619-622 (2000)
[Publications] Seta Y: "Therepy with the nonpeptide endothelin receptor antagonist 97-139 in a murine model of congestive heart failure ; Reduction of cardiac mass and myofiber hypertrophy."J Heart J. 41. 79-85 (2000)
[Publications] Akuzawa N: "Zinc finger transcription factor Egr-1 activates flt-1 gene expression in THP-1 cells on induction for macrophage differentiation."Arterioscler Thromb Vasc Biol. 20. 377-384 (2000)
[Publications] Kaneko K: "C-reactive protein in dilated cardiomyopathy"Cardiology. 91. 215-218 (1999)
[Publications] Takizawa T: "Transcription of the SERCA2 Gene Is Decreased in Pressure Overloaded Hearts : A Study Using In Vivo Direct Gene Transfer into Living Myocardium."J Moll Cell Cardiol. 31. 2167-2174 (1999)
[Publications] Aihara Y: "Molecular cloning of rabbit CARP cDNA and its regulated expression in adriamycin-cardiomyopathy."Biochim Biophys Acta. 1447. 318-324 (1999)
[Publications] Yokoyama T: "Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts"Am J Physiol. 276. H1968-H1976 (1999)
[Publications] Yokoyama T: "Tumor necrosis factor-alpha decreases the phosphorylation levels of phospholamban and troponin I in spontaneously beating rat neonatal cardiac myocytes"J Moll Cell Cardiol. 32. 261-273 (1999)
[Publications] Kanda T: "Increased severity of viral myocarditis in mice lacking lymphocyte maturation"Int J Cardiol. 68. 19-22 (1999)
[Publications] 新井昌史: "遺伝子治療の概要:治療の現況とそれを支える基礎技術"Therapeutic Research. 20. 3017-3028 (1999)
[Publications] 新井昌史: "心血管系への遺伝子導入の進歩-臨床応用の現状"呼吸と循環. 47. 1215-1224 (1999)

2000 Fiscal Year Annual Research Report

遺伝子転写からみた心不全発症機構の解明と治療への応用

Principal Investigator

新井 昌史 群馬大学, 医学部, 講師 (60270857)

Research Products

[Publications] Arai M: "Mechanism of doxorubicin induced inhibition of sarcoplasmic reticulum Ca2+-ATPase gene transcription."Circ Res. 86. 8-14 (2000)

[Publications] Arai M: "Function and regulation of sarcoplasmic reticulum Ca2+-ATPase.Advances during the past decade and prospects for the coming decade."Jpn Heart J. 41. 1-13 (2000)

[Publications] Seta Y: "Interleukin-18 in patients with congestive heart failure : Induction of atrial natriuretic peptide gene rxpression"Molecular Pathology and Pharmacology. (in press). (2000)

[Publications] Seta Y: "Interleukin-18 in acute myocardial infarction"Heart. 84. 668-669 (2000)

[Publications] Aihara Y: "Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy.Role of M-CAT element within the promoter"Hypertension. 35. 48-53 (2000)

[Publications] Oishi Y: "Unclassified connective tissue disease presenting as cardiac tamponade -A case report-"Jpn Circ J. 64. 619-622 (2000)

[Publications] Seta Y: "Therepy with the nonpeptide endothelin receptor antagonist 97-139 in a murine model of congestive heart failure ; Reduction of cardiac mass and myofiber hypertrophy."J Heart J. 41. 79-85 (2000)

[Publications] Akuzawa N: "Zinc finger transcription factor Egr-1 activates flt-1 gene expression in THP-1 cells on induction for macrophage differentiation."Arterioscler Thromb Vasc Biol. 20. 377-384 (2000)

[Publications] Kaneko K: "C-reactive protein in dilated cardiomyopathy"Cardiology. 91. 215-218 (1999)

[Publications] Takizawa T: "Transcription of the SERCA2 Gene Is Decreased in Pressure Overloaded Hearts : A Study Using In Vivo Direct Gene Transfer into Living Myocardium."J Moll Cell Cardiol. 31. 2167-2174 (1999)

[Publications] Aihara Y: "Molecular cloning of rabbit CARP cDNA and its regulated expression in adriamycin-cardiomyopathy."Biochim Biophys Acta. 1447. 318-324 (1999)

[Publications] Yokoyama T: "Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts"Am J Physiol. 276. H1968-H1976 (1999)

[Publications] Yokoyama T: "Tumor necrosis factor-alpha decreases the phosphorylation levels of phospholamban and troponin I in spontaneously beating rat neonatal cardiac myocytes"J Moll Cell Cardiol. 32. 261-273 (1999)

[Publications] Kanda T: "Increased severity of viral myocarditis in mice lacking lymphocyte maturation"Int J Cardiol. 68. 19-22 (1999)

[Publications] 新井昌史: "遺伝子治療の概要:治療の現況とそれを支える基礎技術"Therapeutic Research. 20. 3017-3028 (1999)

[Publications] 新井昌史: "心血管系への遺伝子導入の進歩-臨床応用の現状"呼吸と循環. 47. 1215-1224 (1999)

新井昌史群馬大学, 医学部, 講師 (60270857)