Autophagy in load-induced heart disease.
Autophagy in load-induced heart disease.
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DOI：
10.1161/circresaha.108.186551
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发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Hill, Joseph A.
中科院分区：
文献类型：
--
作者：
Rothermel, Beverly A.;Hill, Joseph A.
心脏是一个高度可塑性的器官，能够根据生理或病理需求的变化进行重塑。例如，当负荷增加时，单个心肌细胞的代偿性肥厚生长会增加心输出量。然而，持续的压力，如高血压或心肌梗死后发生的压力，会引发能量代谢和肌肉蛋白组成的变化，心肌细胞丧失，心室扩张，泵功能降低，最终导致心力衰竭。一段时间以来，人们已经知道自噬在心肌细胞中是活跃的，在疾病中发生的水平增加。现在，随着我们对自噬分子机制的理解的最新进展，心肌细胞自噬对心室重塑和疾病发病机制的潜在贡献正在被探索。作为这项工作的一部分，最近的一些研究集中在血液动力学负荷变化引起的心脏病中的自噬。压力过载应激在适应性不良的心肌细胞中引发强大的自噬反应，导致疾病进展。在这种情况下，负载诱导的细胞内蛋白质聚集是触发自噬清除机制的近端事件。在压力过载的情况下，这些发现与蛋白质伴侣蛋白功能障碍模型中发生的蛋白质聚集形成对比，在蛋白质伴侣蛋白功能障碍模型中，自噬的激活是有益的，可以对抗疾病进展。在这里，我们回顾了最近在负荷性疾病中心肌细胞自噬的研究，并讨论了分子机制和未解之谜。
The heart is a highly plastic organ capable of remodeling in response to changes in physiological or pathological demand. For example, when workload increases, compensatory hypertrophic growth of individual cardiomyocytes occurs to increase cardiac output. Sustained stress, however, such as that occurring with hypertension or following myocardial infarction, triggers changes in energy metabolism and sarcomeric protein composition, loss of cardiomyocytes, ventricular dilation, reduced pump function, and ultimately heart failure. It has been known for some time that autophagy is active in cardiomyocytes, occurring at increased levels in disease. Now, with recent advances in our understanding of molecular mechanisms governing autophagy, the potential contributions of cardiomyocyte autophagy to ventricular remodeling and disease pathogenesis are being explored. As part of this work, several recent studies have focused on autophagy in heart disease elicited by changes in hemodynamic load. Pressure overload stress elicits a robust autophagic response in cardiomyocytes that is maladaptive, contributing to disease progression. In this context, load-induced aggregation of intracellular proteins is a proximal event triggering autophagic clearance mechanisms. These findings in the setting of pressure overload contrast with protein aggregation occurring in a model of protein chaperone malfunction, where activation of autophagy is beneficial, antagonizing disease progression. Here, we review recent studies of cardiomyocyte autophagy in load-induced disease and address molecular mechanisms and unanswered questions.