p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload
p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload
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DOI：
10.1038/nature05602
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发表时间：
2007-03-22
期刊：
影响因子：
64.8
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Sano, Masanori;Minamino, Tohru;Komuro, Issei
心脏肥厚是维持心脏功能的负荷增加后的适应性反应(1)。然而，长期的心脏肥厚导致心力衰竭(2)，其机制在很大程度上是未知的。本研究表明，心脏血管生成在心脏肥厚的适应性机制中起着至关重要的作用，而p53的积累对于心脏肥厚向心力衰竭的转变至关重要。压力过载最初通过缺氧诱导因子-1 （Hif-1）依赖性诱导血管生成因子促进心脏血管生长，抑制血管生成可防止心脏肥厚的发生和诱导收缩功能障碍。持续的压力过载诱导了p53的积累，抑制了Hif-1的活性，从而损害了心脏血管生成和收缩功能。相反，通过引入血管生成因子或抑制p53积累促进血管生成可进一步导致心肌肥大并恢复慢性压力过载下的心功能障碍。这些结果表明，p53的抗血管生成特性可能在心脏肥厚到心力衰竭的转变中起着至关重要的作用。
Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function(1). However, prolonged cardiac hypertrophy causes heart failure(2), and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.