Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy
Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy
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DOI：
10.1161/circulationaha.107.763870
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发表时间：
2008-06-17
期刊：
影响因子：
37.8
通讯作者：
Hill, Joseph A.
中科院分区：
文献类型：
--
作者：
Tannous, Paul;Zhu, Hongxin;Hill, Joseph A.
背景-最近的报道表明，多种形式的心血管应激，包括压力超负荷、慢性缺血和梗死-再灌注损伤，引起心肌细胞自噬活性的增加。然而，没有什么是已知的分子事件，刺激应激心肌自噬活性。由于自噬是一个高度保守的过程，通过它受损的蛋白质和细胞器可以被降解，我们假设，应力诱导的蛋白质聚集是一个近端触发心肌细胞autophagy.Methods和Results-here，我们报告说，压力过载促进积累的泛素化蛋白质聚集在左心室，侵略样结构的发展，和相应的诱导自噬。为了测试因果关系，我们通过抑制蛋白酶体活性来诱导培养的心肌细胞中的蛋白质积累，发现多聚遍在蛋白质的聚集足以诱导心肌细胞自噬。此外，衰减的自噬活性显着提高了侵略的大小和丰度，自噬活性在蛋白质聚集clearance. Conclusions的作用一致，我们得出结论，蛋白质聚集是一个近端触发心肌细胞自噬和自噬活性的功能，以减少聚集/侵略的形成在心脏。本文报道的研究结果首次证明了蛋白质聚集是对血流动力学应激的反应，将压力超负荷性心脏病归入蛋白质病范畴。
Background-Recent reports demonstrate that multiple forms of cardiovascular stress, including pressure overload, chronic ischemia, and infarction-reperfusion injury, provoke an increase in autophagic activity in cardiomyocytes. However, nothing is known regarding molecular events that stimulate autophagic activity in stressed myocardium. Because autophagy is a highly conserved process through which damaged proteins and organelles can be degraded, we hypothesized that stress-induced protein aggregation is a proximal trigger of cardiomyocyte autophagy.Methods and Results-Here, we report that pressure overload promotes accumulation of ubiquitinated protein aggregates in the left ventricle, development of aggresome-like structures, and a corresponding induction of autophagy. To test for causal links, we induced protein accumulation in cultured cardiomyocytes by inhibiting proteasome activity, finding that aggregation of polyubiquitinated proteins was sufficient to induce cardiomyocyte autophagy. Furthermore, attenuation of autophagic activity dramatically enhanced both aggresome size and abundance, consistent with a role for autophagic activity in protein aggregate clearance.Conclusions-We conclude that protein aggregation is a proximal trigger of cardiomyocyte autophagy and that autophagic activity functions to attenuate aggregate/aggresome formation in heart. Findings reported here are the first to demonstrate that protein aggregation occurs in response to hemodynamic stress, situating pressure-overload heart disease in the category of proteinopathies.