Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure
Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure
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DOI：
10.1172/jci24682
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发表时间：
2005-08-01
影响因子：
15.9
通讯作者：
Walsh, K
中科院分区：
文献类型：
--
作者：
Shiojima, I;Sato, K;Walsh, K
虽然增加的外部负荷最初诱导心脏肥大并保持收缩力，但持续的超负荷最终通过知之甚少的机制导致心力衰竭。在这里，我们描述了一个条件性转基因系统的小鼠，其特征在于在心脏中激活的Akt 1基因诱导后，在急性期和慢性期的扩张性心肌病的适应性心脏肥大与保留的收缩力的顺序发展。在适应性心脏生长的急性期，冠状动脉血管生成增强，但随着心脏的病理性重塑而减少。急性期血管生成增强与雷帕霉素依赖性诱导心肌VEGF和血管生成素-2表达的哺乳动物靶点相关。在急性期通过诱饵VEGF受体抑制血管生成导致毛细血管密度降低、收缩功能障碍和心脏生长受损。因此，心脏大小和心脏功能都是血管生成依赖性的，并且心脏中协调的组织生长和血管生成的破坏有助于从适应性心脏肥大到心力衰竭的进展。
Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.