Therapeutic targeting of autophagy: potential and concerns in treating cardiovascular disease.
Therapeutic targeting of autophagy: potential and concerns in treating cardiovascular disease.
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DOI：
10.1161/circresaha.116.303791
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发表时间：
2015-01-30
影响因子：
20.1
通讯作者：
Gustafsson ÅB
中科院分区：
文献类型：
--
作者：
Orogo AM;Gustafsson ÅB
自噬是一个进化上保守的过程，通过该过程，长寿命的蛋白质和细胞器被自噬体隔离，随后被溶酶体降解以进行再循环。自噬对于维持心脏内稳态是重要的，并且是在应激或饥饿期间上调的存活机制。越来越多的证据表明，自噬失调或减少与心力衰竭和衰老有关。因此，调节自噬代表了治疗心血管疾病的有吸引力的未来治疗靶点。自噬的激活通常被认为是心脏保护性的，而过度的自噬可导致细胞死亡和心脏萎缩。重要的是要了解自噬是如何调节的，以确定治疗疾病的理想治疗靶点。在这里，我们讨论了核心自噬机制中的关键蛋白质，并描述了响应细胞外和细胞内信号以紧密协调自噬活性的上游调节因子。我们回顾了各种遗传和药理学研究，证明了自噬在心脏中的重要作用，并考虑了调节自噬方法的优点和局限性。
Autophagy is an evolutionarily conserved process by which long-lived proteins and organelles are sequestered by autophagosomes and subsequently degraded by lysosomes for recycling. Autophagy is important for maintaining cardiac homeostasis and is a survival mechanism that is upregulated during stress or starvation. Accumulating evidence suggests that dysregulated or reduced autophagy is associated with heart failure and aging. Thus, modulating autophagy represents an attractive future therapeutic target for treating cardiovascular disease. Activation of autophagy is generally considered to be cardioprotective, while excessive autophagy can lead to cell death and cardiac atrophy. It is important to understand how autophagy is regulated to identify ideal therapeutic targets for treating disease. Here, we discuss the key proteins in the core autophagy machinery and describe upstream regulators that respond to extracellular and intracellular signals to tightly coordinate autophagic activity. We review various genetic and pharmacological studies that demonstrate the important role of autophagy in the heart and consider the advantages and limitations of approaches that modulate autophagy.