Jimenez Rebecca E, Kubli Dieter A, Gustafsson Åsa B
Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Br J Pharmacol. 2014 Apr;171(8):1907-16. doi: 10.1111/bph.12477.
The autophagic-lysosomal degradation pathway is critical for cardiac homeostasis, and defects in this pathway are associated with development of cardiomyopathy. Autophagy is responsible for the normal turnover of organelles and long-lived proteins. Autophagy is also rapidly up-regulated in response to stress, where it rapidly clears dysfunctional organelles and cytotoxic protein aggregates in the cell. Autophagy is also important in clearing dysfunctional mitochondria before they can cause harm to the cell. This quality control mechanism is particularly important in cardiac myocytes, which contain a very high volume of mitochondria. The degradation of proteins and organelles also generates free fatty acids and amino acids, which help maintain energy levels in myocytes during stress conditions. Increases in autophagy have been observed in various cardiovascular diseases, but a major question that remains to be answered is whether enhanced autophagy is an adaptive or maladaptive response to stress. This review discusses the regulation and role of autophagy in the myocardium under baseline conditions and in various aetiologies of heart disease. It also discusses whether this pathway represents a new therapeutic target to treat or prevent cardiovascular disease and the concerns associated with modulating autophagy.
自噬-溶酶体降解途径对心脏稳态至关重要，该途径的缺陷与心肌病的发展相关。自噬负责细胞器和长寿命蛋白质的正常周转。自噬也会在应激反应中迅速上调，在此过程中它会迅速清除细胞内功能失调的细胞器和细胞毒性蛋白聚集体。自噬在清除功能失调的线粒体以免其对细胞造成损害方面也很重要。这种质量控制机制在含有大量线粒体的心肌细胞中尤为重要。蛋白质和细胞器的降解还会产生游离脂肪酸和氨基酸，有助于在应激条件下维持心肌细胞的能量水平。在各种心血管疾病中均观察到自噬增加，但一个有待解答的主要问题是增强的自噬是对应激的适应性还是适应不良性反应。本综述讨论了在基线条件下以及在各种心脏病病因中自噬在心肌中的调节和作用。它还讨论了该途径是否代表治疗或预防心血管疾病的新治疗靶点以及与调节自噬相关的问题。
