Inhibition of ischemia induced-apoptosis in cardiac myocytes by ATF3 and its implication in gene therapy

• Project/Area Number: 13670696
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ITO Hiroshi M. D., Department of Cardiovascular Medicine The Graduate School of Medicine and Dentistry Tokyo Medical and Dental University, Associate Professor, 大学院・医歯学総合研究科, 助教授 (10232464)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: ATF3 / doxorubicin / myocardial ischemia / reperfusion / c-jun / AP-1 / p53 / アポトーシス / アデノウイルスベクター

Research Abstract

ATF3 (activating transcription factor 3) is a member of the ATF/CREB family, which binds to CRE and AP-1 consensus sequences. We have recently reported that ATF3 inhibits apoptosis of cultured neonatal rat cardiac myocytes induced by DOX. ATF3 was immediately induced at transcriptional and translational level by stimulation of DOX, peaking at 1 hour and at 3 hours respectively. To extend our understanding of the physiological functions of ATF3 in the DOX-induced apoptosis, we produced the adenovirus vector containing coding sequences of ATF3 (AdATF3) and directed overexpression of ATF3 in cardiac myocytes. The inhibition of DOX-induced apoptosis by AdATF3 was shown by flow cytometry, cefi viabih'ty assay and TUNEL staining analyzes. We further demonstrated that ATF3 formed heterodimer with c-Jun both in the cells with or without DOX treatment, suggesting that inappropriate formation of hetero- and homodimer of ATF3 may result in the inhibition of apoptosis in cardiac myocytes with AdATF3.
We further investigated AdATF3 can inhibit apoptosis induced by ischemia in cardiac myocytes. AdATF3 inhibited apoptosis induced by hypoxic stimulation in vitro. We also showed that AdATF3 inhibited apoptosis induced by ischemia-reperfusion.
In conclusion, these results indicate that overexpression of ATF3 inhibits apoptosis in cardiac myocytes, and suggest a cardio protective role of ATF3. Our data may open a new avenue for gene therapy against myocardial damage by a variety of cardiovascular diseases.

Research Products

• [Publications] Tamamori-Adachi M, Ito, H., S.Piyamas, 他: "Critical role of Cyclin D1 nuclear import in cardiomyocyte proliferation"Circ Res.. 92. 12-19 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tamamori-Adachi M, Ito H, Nobori K 他: "Expression of cyclin D1 and CDK4 causes hypertrophic growth of cardiomyocytes in cuture : a possible implication for cardiac hypertrophy"Biochem. Biophys. Res Commun.. 296(2). 274-280 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nobori K, Ito H, Tamamori-Adachi M 他: "ATF3 Inhibits Doxorubicin-induced Apoptosis in Cardiac Myocytes : A Novel Cardioprotective Role of ATF3"J. Mol. Cell Cardiol.. 34. 1387-1392 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nozato T, Ito H, Watanabe M 他: "Overexpression of cdk inhibitor p16^<INK4a> by adenovirus vector inhibits cardiac hypertrop in vitro and in vivo : a novel strategy for the gene therapy of cardiac hypertrophy"J. Mol. Cell Cardiol.. 33. 1493-1504 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Adachi S, Ito H, Tamamori M: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes"Circ Res. 88. 408-414 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tamanori-Adachi M, Ito H, S Piyamas, Adachi S, Hiroe M, Shimizu M, Kawauchi J, Sunamori M, Marumo F, Kitajima S, Ikeda M Tamamori-Adachi M, Ito H, S Piyamas et al.: "Critical role of Cyclin Dl nuclear import in cardiomyocyte proliferation"Circ Res.. 92. 12-19 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tamamori-Adachi M, Ito H. Nobori K, Hayashida K, Kawauchi J, Adachi S, Ikeda M, Kitajima S: "Expression of cyclin Dl and CDK4 causes hypertrophic growth of cardiomyocytes in culture a possible implication for cardiac hypertrophy"Biochem. Biophys. Res. Commun.. 296(2). 274-280 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nobori K, Ito H. Tamamori-Adachi M, Adachi S, Ono Y, Kawauchi J, Kitajima S, Marumo F, Isobe M: "ATF3 Inhibits Doxorubicin-induced Apoptosis in Cardiac Myocytes : A Novel Cardioprotective Role of ATF3"J. Mol. Cell Cardiol.. 34. 1387-1392 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nozato T, Ito H, Watanabe M, Ono Y, Adachi S, Tanaka H, Hiroe M, Sunamori M, Marumo M: "Overexpression of cdk inhibitor p16^<INK4a> by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo : a novel strategy for the gene therapy of cardiac hypertrophy"J. Mol. Cell Cardiol.. 33. 1493-1504 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Adachi S, Ito H, Tamamori M, Ono Y, Nozato T, Abe S, Ikeda M, Marumo F, Hiroe M: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes"Circ Res. 88. 408-414 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tamamori-Adachi M, Ito H, S Piyamas, 他: "Critical role of Cyclin D1 nuclear import in cardiomyocyte proliferation"Circ Res.. 92. 12-19 (2003)
• [Publications] Tamamori-Adachi M, Ito H, Nobori K, 他: "Expression of cyclin D1 and CDK4 causes hypertrophic growth of cardiomyocytes in cuture : a possible implication for cardiac hypertrophy"Biochem. Biophys. Res Commun.. 296(2). 274-280 (2002)
• [Publications] Nobori K, Ito H, Tamamori-Adachi M, 他: "ATF3 Inhibits Doxorubicin-induced Apoptosis in Cardiac Myocytes : A Novel Cardioprotective Role of ATF3"J. Mol. Cell Cardiol. 34. 1387-1392 (2002)
• [Publications] Nozato T, Ito H, Watanabe M, 他: "Overexpression of cdk inhibitor pl6^<INK4a> by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo : a novel strategy for the gene therapy of cardiac hypertrophy"J. Mol. Cell Cardiol. 33. 1493-1504 (2001)
• [Publications] Adachi S, Ito H, Tamamori M: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes"Circ Res. 88. 408-414 (2001)
• [Publications] Nobori K, Ito H, Tamamori-Adachi M, Adachi S, Ono Y, et al.: "ATF3 Inhibits Doxorubicin-induced Apoptosis in Cardiac Myocytes ; A Novel Cardiorotective Role of ATF3"J. Mol. Cell Cardiol. (in press). (2002)
• [Publications] Nozato T, Ito H, Watanabe M, Ono Y Adachi S, Tanaka H, et al.: "Overexpression of cdk inhibitor p16^<INK4a>by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo : a novel strategy for therapy of cardiac hypertrophy"J. Mol. Cell Cardiol.. 33. 1493-1504 (2001)
• [Publications] Adahi S, Ito H, Tamamori M, Ono Y, Nozato T, Abe S, et al.: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes"Ciro Res. 88. 408-414 (2001)