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Molecular mechanisms of heart failure and their therapeutic implications revealed by inducible transgenic mice

诱导转基因小鼠揭示心力衰竭的分子机制及其治疗意义

基本信息

批准号：
18390228
负责人：
SHIOJIMA Ichiro
金额：
$ 11.36万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390228/
关键词：
cardiac hypertrophy heart failure Akt coronary angiogenesis

项目摘要

Using cardiac-specific inducible Aktl transgenic mice, the following points were investigated. 1) Mechanism of the transition from pathological cardiac hypertrophy to heart failure Pathological cardiac hypertrophy was induced by long-term Akt activation in the heart. In this experimental condition, coronary capillary density was reduced and VEGF expression in the heart normally observed in physiological hypertrophy was missing, suggesting that hypoxia in the myocardium contributes to the transition from adaptive cardiac hypertrophy to heart failure. Induction of VEGF expression in physiological hypertrophy was blunted by mTOR inhibitor rapamycin. Thus, dysregulation of Akt-mTOR pathway in the heart may play a causal role in the progression of heart failure under pathological stress. 2) Molecular disntinction between physiological versus pathological cardiac hypertrophy To identify the molecular signature that determines the differences between physiological and pathological cardiac hyp … More ertrophy, DNA microarray analysis was performed to isolate mRNAs that are differentially expressed between these two distinct forms of cardiac hypertrophy. Among differentially expressed genes, we found that molecules involved in fatty acid metabolism were downregulated in the heart with pathological hypertrophy. The expression of PPARγ and PGC-1α, key transcription factors that regulate the expression of fatty acid oxidation genes, were also downregulated by short-term Akt activation, suggesting that Akt regulates cardiac function by modulating glucose/fatty acid metabolism. 3) Therapeutic implications of Akt activation in diseased hearts Short-term Akt activation induces physiological form of cardiac hypertrophy with maintained contractility and increased expression of VEGF in the myocardium. To test the hypothesis that short-term Akt activation improves cardiac function in heart failure. Heart failure was induced by two methods, pressure overload by aortic constriction, and injection of cardiotoxic anti-tumor drug doxorubicin. In both cases, Akt transgene expression was induced when heart failure was established. Short-term Akt activation in these experimental settings improved contractile function, suggesting that Akt activation may be a novel therapeutic strategy for heart failure. Less

使用心脏特异性诱导型Aktl转基因小鼠，研究了以下几点。1)病理性心肌肥大向心力衰竭转变的机制病理性心肌肥大是由心脏中Akt的长期激活诱导的。在该实验条件下，冠状动脉毛细血管密度降低，并且在生理性肥大中通常观察到的心脏中的VEGF表达缺失，表明心肌中的缺氧有助于从适应性心脏肥大向心力衰竭的转变。mTOR抑制剂雷帕霉素减弱了生理性肥大中VEGF表达的诱导。因此，心脏中Akt-mTOR通路的失调可能在病理应激下心力衰竭的进展中起因果作用。2)生理性与病理性心肌肥厚的分子鉴别 ...更多信息为了研究心肌肥大，进行DNA微阵列分析以分离在这两种不同形式的心肌肥大之间差异表达的mRNA。在差异表达基因中，我们发现参与脂肪酸代谢的分子在病理性肥大的心脏中下调。调节脂肪酸氧化基因表达的关键转录因子PPARγ和PGC-1α的表达也被短期Akt激活下调，表明Akt通过调节葡萄糖/脂肪酸代谢来调节心脏功能。3)Akt激活在患病心脏中的治疗意义短期Akt激活诱导生理形式的心脏肥大，具有维持的收缩性和心肌中VEGF表达增加。验证短期Akt激活改善心力衰竭患者心功能的假设。心力衰竭通过两种方法诱导，通过主动脉收缩的压力超负荷和注射心脏毒性抗肿瘤药物阿霉素。在这两种情况下，Akt转基因表达诱导心力衰竭时建立。在这些实验环境中，短期Akt激活改善了收缩功能，表明Akt激活可能是心力衰竭的新治疗策略。少