Molecular Mechanism of STAT3 in Cardiac development and Differentiation

• Project/Area Number: 12835006
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Institution: Osaka University
• Principal Investigator: HIROTA Hisao Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30273684)
• Co-Investigator(Kenkyū-buntansha): TAKIHARA Keiko Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70252640)
• Project Period (FY): 2000 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥3,700,000 (Direct Cost: ¥3,700,000); Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: gp130 / STAT3 / BMP-2 / SMAD1 / GP130 / SMAD1 / VEGF / ジーンターゲッティングマウス

Research Abstract

1. Cardiac fibrosis. is a consequence of remodeling processes, which leads to abnormal myocardial stiffness and ventricular dysfunction. Signal transducer transducer and activator of transcription 3 (STAT3) functions in cardiac cell hypertrophy and survival. However, its precise factional significance has been undefined. In this paper, we report the generation of mice with cardiac-specific disruption of STAT3 (STAT3CKO).
We observed multifocal fibrobe tenon, in the ventricles from STAT3CKO. The expression of TGFβ1 and 3 are increased in STAT3CKO heart. This study establishes STAT3 as an antifibrotic factor in vivo and provides evidence for its role as a local regulator of ventricular remodeling.
2. We reported that the activation of STATs by LIf (leukemia inhibitory factor) or Smads by BMP2 (bone morphogenetic proteins-2) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes (CM). Recently, BMP2 and LIF were shown to act in synergy on primary fetal neural progenitor cel ls to induce astrocytes.
Therefore, we investigated whether the synergistic crosstalk between BMP2 and LIF on doxorubicin (DCX)-induced apoptosis in cultured neonatal rat CM. We added BMP2 (80 ng/ml), LIf (Ix10^3 U/ml) and BMP2 plos LIF in CM.
We performed an MTS respiration assay to measure cell viability against DOX-induced apoptosis. BMP2 plus LIF functioned in synergy to promote myocardial cell survival, comparing with BMP alone or LIF alone.
By northern blotting and western blotting, we also showed that BMP2 plus LIF synergistically induced the expression of bcl-xL mRNA and protein. In order to investigate the mechanism on the synergistic action, we checked intercellular signaling in CM Interestingly, BMP2 plus LIF induced synergistic phosphorylation in Smadl, not in STAT3. On the other hand, MAP kinase family including ERK1/2 and JNK were not significantly enhanced.
Our findings suggest that BMP2 acts in synergy with LIf to inhibit DOX-induced apoptosis through the induction of smadl-bcl-xlin in CM.

Research Products

• [Publications] M.Funamoto et al.: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mendiated induction of vascular endothelial growth factor in cardiac myocytes"J Biol Chem. 275. 10561-10566 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] M.Izumi et al.: "Bone morphogenic protein-2 inhibits serun deprivation-induced apoptpsis of neonatal cardiac myocytes through the actvation of smad1 pathway"J Biol Chem. 276. 31133-31141 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] S.Negoro et al.: "Activation of STAT3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganess superoxide dismutase"Circulation. 104. 979-981 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] T.Osugi et al.: "Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vasCular formation in the heart"J Biol Chem. 277. 6676-6681 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] K.Kunisada et al.: "Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation"Cardiovasc Res. (in press). (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] M. Funamoto et al.: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mendiated induction of vascular endothelial growth factor in cardiac myocytes"J. Biol. Chem.. 275. 10561-10566 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] M. Izumi et al.: "Bone morphogenic protein-2 inhibits serum deprivation-induced apoptosis of neonatal cardiac myocytes through the activation of smadl pathway"J. Biol. Chem.. 276. 31133-31141 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] S. Negoro et al.: "Activation of STAT3 protects cardiomyocytes from hypoxia reoxygenation-induced oxidative stress through the upregulation of managanese superoxide dismutase"Circulation. 104. 979-981 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] T. Osugi et al.: "Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart"J. Biol. Chem.. 277. 6676-6681 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] K. Kunisada et al.: "Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation"Cardiovasc Res. (in press). (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] M.Izumi et al.: "Bone morphogenic protein-2 inhibits serum deprivation-induced apoptosis of neonatal cardiac myocytes through the activation of smad1 pathway"J Biol Chem. 276. 31133-31141 (2001)
• [Publications] S.Negoro et al.: "Activation of STAT3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase"Circulation. 104. 979-981 (2001)
• [Publications] T.Osugi et al.: "Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart"J Biol Chem. 277. 6676-6681 (2002)
• [Publications] K.Kunisada et al.: "Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation"Cardiovasc Res. (in press). (2002)
• [Publications] M.Funamoto et al.: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mendiated induction of vascular endothelial growth factor in cardiac myocytes."J.Biol.Chem.. 275. 10561-10566 (2000)