Abstract
Autophagy is a subcellular process that plays an important role in the degradation of proteins and damaged organelles such as mitochondria (a process termed “mitophagy”) via lysosomes. It is crucial for regulating protein and mitochondrial quality control and maintaining cellular homeostasis, whereas dysregulation of autophagy has been implicated in a wide range of diseases including atherosclerosis. Recent evidence has shown that the autophagic process becomes dysfunctional during the progression of atherosclerosis, regardless of whether there are many autophagy-stimulating factors (e.g., reactive oxygen species, oxidized lipids, and cytokines) present within the atherosclerotic plaque. This review highlights the recent insights into the causes and consequences of defective autophagy in atherosclerosis, with a special focus on the role of autophagy and mitophagy in plaque macrophages, vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). It has been shown that defective autophagy can promote apoptosis in macrophages but that it accelerates premature senescence in VSMCs. In the ECs, defective autophagy promotes both apoptosis and senescence. We will discuss the discrepancy between these three cell types in their response to autophagy deficiency and underline the cell type-dependent role of autophagy, which may have important implications for the efficacy of autophagy-targeted treatments for atherosclerosis.
Highlights
Atherosclerosis is a chronic inflammatory disease which is characterized by the formation of lipid-containing plaques in the vessel wall of large- and medium-sized arteries [1, 2]
Atherosclerotic plaque stability is maintained by the formation of a thick fibrous cap overlaying a large necrotic core of oxidized lipids and necrotic debris derived from vascular smooth muscle cells (VSMCs) and macrophages
Multiple lines of evidence have suggested that autophagy becomes dysfunctional during the progression of atherosclerosis; the investigation of its consequences on plaque stability has been of great importance
Summary
Atherosclerosis is a chronic inflammatory disease which is characterized by the formation of lipid-containing plaques in the vessel wall of large- and medium-sized arteries [1, 2]. They preferentially develop at branching points where blood flow is low/disrupted and the barrier function of the endothelial cell (EC) layer is compromised. The nucleation and elongation of autophagosomes are directed by specific autophagy-related (ATG) proteins such as ATG5 and ATG7 These proteins are in turn regulated by multiple upstream signaling factors, such as the mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). We will discuss the role of autophagy in atherosclerosis, with a special focus on the impact of defective autophagy on plaque macrophages, VSMCs, and ECs
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