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

利用心脏特异性诱导Aktl转基因小鼠，研究了以下几点。1)病理性心肌肥厚向心力衰竭转变的机制：心脏内长期激活Akt诱导病理性心肌肥厚。在本实验条件下，冠状动脉毛细血管密度降低，生理性肥厚中正常观察到的心脏血管内皮生长因子表达缺失，提示心肌缺氧参与了适应性肥厚向心力衰竭的转变。mTOR抑制剂雷帕霉素对生理性肥大中VEGF表达的诱导作用减弱。因此，心脏中Akt-mTOR通路的失调可能在病理性应激下心力衰竭的进展中起因果作用。2)生理性和病理性心肌肥厚的分子区别为了确定决定生理性和病理性心肌肥厚差异的分子特征，我们进行了DNA微阵列分析，分离出这两种不同形式的心肌肥厚差异表达的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。调控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Akt短期激活下调，提示Akt通过调节葡萄糖/脂肪酸代谢来调节心功能。3) Akt激活在病变心脏中的治疗意义短期Akt激活可诱导生理形式的心肌肥厚，保持心肌收缩力并增加心肌中VEGF的表达。验证短期激活Akt可改善心力衰竭患者心功能的假说。采用主动脉收缩引起的压力过载和注射抗肿瘤药物阿霉素两种方法诱发心力衰竭。在这两种情况下，在心力衰竭建立时诱导Akt基因表达。在这些实验环境中，短期激活Akt可改善收缩功能，这表明激活Akt可能是治疗心力衰竭的一种新策略。少

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