Defective Autophagy in Atherosclerosis: To Die or to Senesce?

Figure 1

Role of autophagy in macrophages, vascular smooth muscle cells, and endothelial cells in atherosclerosis. (a) Oxidized lipids (e.g., oxLDL and 7-ketocholesterol) present in atherosclerotic plaques can stimulate autophagy in macrophages (MΦ) in either a direct manner or indirectly through induction of ER stress. Degradation of damaged proteins and organelles in the autophagosome favors cell survival. Specific removal of dysfunctional mitochondria by mitophagy also limits inflammation. Macrophage autophagy also promotes cholesterol efflux by regulating the delivery of lipid droplets to lysosomes. (b) Autophagy in vascular smooth muscle cells (VSMCs) can be triggered by various atherosclerosis-related stimuli such as oxLDL, 7-ketocholesterol, 4-hydroxynonenal, osteopontin, and TNFα. oxLDL activates mitophagy in VSMCs as a safeguarding mechanism against apoptosis. VSMC autophagy may also be stimulated by the growth factor PDGF that promotes the development of a synthetic, hyperproliferative VSMC phenotype. (c) Autophagy/mitophagy in ECs can be stimulated by different atherogenic stimuli such as oxLDL, AGEs, and saturated fatty acids to promote EC survival. Upon oxLDL exposure, autophagy is activated either directly or indirectly through induction of ER stress and facilitates oxLDL degradation. Also exposure to high shear stress stimulates protective autophagy in ECs. (d) Defective autophagy in macrophages (e.g., by Atg5 deficiency) results in accumulation of damaged proteins and organelles, such as mitochondria, which leads to increased oxidative stress (1) and apoptosis (2). Apoptotic autophagy-deficient macrophages are not properly phagocytized (3). Autophagy-defective macrophages are further characterized by hyperactivation of the inflammasome (4) and impaired cholesterol efflux (5). (e) Defective autophagy in VSMCs (e.g., by Atg7 deficiency) leads to accumulation of p62, resulting in activation of the Nrf2 antioxidative pathway (1) and p16/pRB-mediated cellular senescence (2). Autophagy-deficient VSMCs are characterized by cellular and nuclear hypertrophy (3), increased SAβG activity (4), collagen deposition (5), increased secretion of promigratory factors (TGFβ, MMP9, and SDF1) (6), and decreased proliferation (7). (f) Exposure of ECs to low/disturbed shear stress impairs autophagy. Autophagy deficiency in ECs (e.g., by Atg5 or Atg7 deficiency) promotes apoptosis (1) and senescence (2). Autophagy-deficient ECs are also characterized by defective oxLDL degradation (3) and increased inflammation (4). 4-HNE: 4-hydroxynonenal; 7-KC: 7-ketocholesterol; AP: autophagosome; ER: endoplasmic reticulum; LYS: lysosomes; NU: nucleus; OP: osteopontin; ROS: reactive oxygen species; AGEs: advanced glycation end products.