Class III PI3K-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure.
Class III PI3K-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure.
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III类PI3K介导的自噬延长激活在心脏肥大向心力衰竭的转变中发挥关键作用
DOI：
10.1111/jcmm.12547
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发表时间：
2015-07
影响因子：
5.3
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Yu P;Zhang Y;Li C;Li Y;Jiang S;Zhang X;Ding Z;Tu F;Wu J;Gao X;Li L
病理性心肌肥厚常导致心力衰竭。在病理性肥厚的心脏中已经显示了自噬的激活。自噬受III型磷脂酰肌醇3-激酶(PI3K)正向调节。然而，尚不清楚III类PI3K是否在心肌肥厚向心力衰竭的转变中起作用。为了解决这个问题，我们采用了先前在热休克蛋白27转基因小鼠中建立的心肌肥大模型，该模型具有几种类型的人类心肌病的共同特征。以年龄匹配的野生型小鼠为对照。首先，从适应性阶段到非适应性阶段，肥厚心脏的自噬激活时间延长，表现为自噬小体积累、Lc3转化率增加和p62蛋白水平降低。此外，在自噬小体堆积的区域，肌丝和线粒体出现了形态异常。其次，在从适应性阶段到非适应性阶段的肥厚心脏中，表现为Vps34的表达上调，Vps34与Beclin-1的相互作用增加，而Bcl2的表达降低，从而激活了III类PI3K空泡蛋白分类34(Vps34)。最后，Wortmaninn是一种广泛使用的自噬抑制剂，通过抑制Class III PI3K活性，显著降低了自噬活性，改善了细胞内公寓的形态，最重要的是，防止了肥厚心脏的进行性心功能障碍。总而言之，在本研究中，我们证明了III类PI3K通过延长自噬的激活，在心肌肥厚向心力衰竭的转变中起着核心作用。III类PI3K可作为治疗和管理适应性不良心肌肥厚的潜在靶点。
Pathological cardiac hypertrophy often leads to heart failure. Activation of autophagy has been shown in pathological hypertrophic hearts. Autophagy is regulated positively by Class III phosphoinositide 3-kinase (PI3K). However, it is unknown whether Class III PI3K plays a role in the transition of cardiac hypertrophy to heart failure. To address this question, we employed a previously established cardiac hypertrophy model in heat shock protein 27 transgenic mice which shares common features with several types of human cardiomyopathy. Age-matched wild-type mice served as control. Firstly, a prolonged activation of autophagy, as reflected by autophagosome accumulation, increased LC3 conversion and decreased p62 protein levels, was detected in hypertrophic hearts from adaptive stage to maladaptive stage. Moreover, morphological abnormalities in myofilaments and mitochondria were presented in the areas accumulated with autophagosomes. Secondly, activation of Class III PI3K Vacuolar protein sorting 34 (Vps34), as demonstrated by upregulation of Vps34 expression, increased interaction of Vps34 with Beclin-1, and deceased Bcl-2 expression, was demonstrated in hypertrophic hearts from adaptive stage to maladaptive stage. Finally, administration with Wortmaninn, a widely used autophagy inhibitor by suppressing Class III PI3K activity, significantly decreased autophagy activity, improved morphologies of intracellular apartments, and most importantly, prevented progressive cardiac dysfunction in hypertrophic hearts. Collectively, we demonstrated that Class III PI3K plays a central role in the transition of cardiac hypertrophy to heart failure via a prolonged activation of autophagy in current study. Class III PI3K may serve as a potential target for the treatment and management of maladaptive cardiac hypertrophy.