2004 Fiscal Year Final Research Report Summary
A novel strategy for the treatment of congestive heart failure utilizing thyroid hormone signaling
| Project/Area Number |
15590723
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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 Field |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KINUGAWA Koichiro The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (00345216)
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| Co-Investigator(Kenkyū-buntansha) |
YAO Atsushi The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (70372381)
TAKAHASHI Toshiyuki The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (40236302)
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| Project Period (FY) |
2003 – 2004
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| Keywords | thyroid hormone / cardiac myocytes / cardiac hypertrophy / p38 MAK kinase / thyroid hormone receptor / fetal gene program / adenovirus / rat |
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| Research Abstract |
We investigated the effects of over-expression of thyroid hormone receptors (TRs) using adenoviral vector in cultured neonatal rat cardiac myocytes. Over-expression of TRβ1 inhibited myocyte hypertrophy, which was accompanied by decreased phosphorylation of p38 MAP kinase. The attenuated phosphorylation of p38 was attributable to the negative interaction between TRb1 and p38α. Over-expression of TRβ1, however, resulted in the pattern of adult type gene expression which was characteristic of thyroid hormone treatment, i.e. increases in αMHC and SERCA, decreases in βMHC mRNA. Over-expression of TRβ1 also induced endogenous TRβ1 expression. We next examined the effects of GC-1, a TRβ-specific agonist in cultured myocytes. GC-1 was less potent in the induction of cardiac hypertrophy than T3, but induced adult gene expression (increased αMHC and SERCA, decreased βMHC) at the similar level observed in the case of T3. One of co-investigator, John Baxter reported that GC-1 was less associated with tachycardia, and induced good lipid profile similar to T3 because cholesterol 7a-hydroxylase was specifically regulated by TRβ1 in liver. The observation suggests that TRb-specific agonist has a potential for better outcome in the treatment of congestive heart failure, by means of re-induction of efficient adult isoform without tachycardia. On the other hand, we observed marked cardiac hypertrophy by the over-expression of TRa1, which was accompanied by fetal gene program. The pathologic hypertrophy by TRa1 was attributable to the activation of p38 MAP kinase cascade. We found that TRa1 interacted with TAK1 which was an upstream molecule in the signaling of p38. Therefore, thyroid hormone signaling has dual pathways in cardiac myocytes, i.e. TRa1 leads to hypertrophy, TRb1 causes adult gene expression, and the two pathways balance after stimulated by thyroid hormone.
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Research Products
(6 results)
