Department of Medicine, Columbia University, New York, NY 10032, USA.
Cell Metab. 2012 Apr 4;15(4):545-53. doi: 10.1016/j.cmet.2012.01.022. Epub 2012 Mar 22.
In advanced atherosclerosis, macrophage apoptosis coupled with defective phagocytic clearance of the apoptotic cells (efferocytosis) promotes plaque necrosis, which precipitates acute atherothrombotic cardiovascular events. Oxidative and endoplasmic reticulum (ER) stress in macrophages are important causes of advanced lesional macrophage apoptosis. We now show that proapoptotic oxidative/ER stress inducers trigger another stress reaction in macrophages, autophagy. Inhibition of autophagy by silencing ATG5 or other autophagy mediators enhances apoptosis and NADPH oxidase-mediated oxidative stress while at the same time rendering the apoptotic cells less well recognized by efferocytes. Most importantly, macrophage ATG5 deficiency in fat-fed Ldlr(-/-) mice increases apoptosis and oxidative stress in advanced lesional macrophages, promotes plaque necrosis, and worsens lesional efferocytosis. These findings reveal a protective process in oxidatively stressed macrophages relevant to plaque necrosis, suggesting a mechanism-based strategy to therapeutically suppress atherosclerosis progression and its clinical sequelae.
在动脉粥样硬化的晚期，巨噬细胞凋亡伴随着对凋亡细胞（吞噬作用）的清除缺陷，促进斑块坏死，从而引发急性动脉粥样硬化性心血管事件。巨噬细胞中的氧化和内质网（ER）应激是晚期病变巨噬细胞凋亡的重要原因。我们现在表明，促凋亡的氧化/ER 应激诱导剂在巨噬细胞中引发另一种应激反应，自噬。通过沉默 ATG5 或其他自噬介质抑制自噬会增强细胞凋亡和 NADPH 氧化酶介导的氧化应激，同时使凋亡细胞更难被吞噬细胞识别。最重要的是，在高脂肪饮食喂养的 Ldlr(-/-) 小鼠中，巨噬细胞 ATG5 缺失会增加晚期病变巨噬细胞中的细胞凋亡和氧化应激，促进斑块坏死，并加重病变部位的吞噬作用缺陷。这些发现揭示了与斑块坏死相关的氧化应激巨噬细胞中的一种保护过程，提示了一种基于机制的策略来治疗性抑制动脉粥样硬化的进展及其临床后果。
