Proteotoxicity and cardiac dysfunction.
Proteotoxicity and cardiac dysfunction.
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DOI：
10.1161/circresaha.116.305372
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发表时间：
2015-05-22
影响因子：
20.1
通讯作者：
Robbins J
中科院分区：
文献类型：
--
作者：
McLendon PM;Robbins J
哺乳动物心脏的基线生理功能处于环境或内在病理损伤的持续威胁下。因此，心肌细胞蛋白质受到持续的压力，以发挥最佳功能，这取决于它们采取和保持适当的构象。这篇综述探讨了多种防御细胞可能采用其蛋白质承担和维持正确的蛋白质折叠和构象。存在多种质量控制机制以确保新生多肽正确折叠并且成熟蛋白质保持其功能构象。当蛋白质发生错误折叠时，无论是在正常或病理刺激下，还是由于内在突变或翻译后修饰，它们必须正确重折叠或回收。如果没有这些纠正过程，它们可能对细胞有毒。在此，我们探讨一些潜在的机制，导致蛋白毒性。错误折叠或未折叠蛋白质的持续存在和慢性积累在心肌细胞中可能是灾难性的，因为这些错误折叠蛋白质可能导致聚集或形成蛋白毒性的可溶性肽。这反过来又导致蛋白质质量控制受损，并促使细胞维持蛋白质稳态的能力呈螺旋式下降。一些潜在的机制进行了讨论，并探讨了在心脏中的蛋白毒性干扰的治疗潜力。
Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.