Shiojima Ichiro, Sato Kaori, Izumiya Yasuhiro, Schiekofer Stephan, Ito Masahiro, Liao Ronglih, Colucci Wilson S, Walsh Kenneth
Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
J Clin Invest. 2005 Aug;115(8):2108-18. doi: 10.1172/JCI24682.
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.
尽管增加的外部负荷最初会诱导心脏肥大且收缩力保持不变，但持续的超负荷最终会通过尚不清楚的机制导致心力衰竭。在此，我们描述了一种小鼠条件转基因系统，其特征是在心脏中诱导激活的Akt1基因后，急性期出现适应性心脏肥大且收缩力保持不变，慢性期则发展为扩张型心肌病。在适应性心脏生长的急性期，冠状动脉血管生成增强，但随着心脏发生病理重塑而减少。急性期血管生成增强与雷帕霉素哺乳动物靶标依赖性诱导心肌VEGF和血管生成素-2表达有关。在急性期用诱饵VEGF受体抑制血管生成会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均依赖于血管生成，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发展为心力衰竭。
