2001 Fiscal Year Final Research Report Summary
Molecular Mechanism of STAT3 in Cardiac development and Differentiation
| Project/Area Number |
12835006
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Institution | Osaka University |
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Principal Investigator |
HIROTA Hisao Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30273684)
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| Co-Investigator(Kenkyū-buntansha) |
TAKIHARA Keiko Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70252640)
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| Project Period (FY) |
2000 – 2001
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| Keywords | gp130 / STAT3 / BMP-2 / SMAD1 |
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| 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
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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. Less
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Research Products
(10 results)
