Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disorder characterized by the gradual buildup of plaques within the vessel wall of middle-sized and large arteries. The occurrence and development of atherosclerosis and the rupture of plaques are related to the injury of vascular cells, including endothelial cells, smooth muscle cells, and macrophages. Autophagy is a subcellular process that plays an important role in the degradation of proteins and damaged organelles, and the autophagy disorder of vascular cells is closely related to atherosclerosis. Pyroptosis is a proinflammatory form of regulated cell death, while ferroptosis is a form of regulated nonapoptotic cell death involving overwhelming iron-dependent lipid peroxidation. Both of them exhibit distinct features from apoptosis, necrosis, and autophagy in morphology, biochemistry, and genetics. However, a growing body of evidence suggests that pyroptosis and ferroptosis interact with autophagy and participate in the development of cancers, degenerative brain diseases and cardiovascular diseases. This review updated the current understanding of autophagy, pyroptosis, and ferroptosis, finding potential links and their effects on atherogenesis and plaque stability, thus providing ways to develop new pharmacological strategies to address atherosclerosis and stabilize vulnerable, ruptured plaques.

Keywords: atherosclerosis; autophagy; cell death; ferroptosis; pyroptosis.

FIGURE 1

Effects of autophagy on atherosclerosis. Autophagy dysfunction induces endothelial dysfunction and inflammation, promoting monocyte recruitment and cell death. Autophagy dysfunction aggravates plaque instability and promotes the formation of foam cells by influencing VSMC death and phenotypic conversion. Autophagy dysfunction induces lipid accumulation, macrophage foam cell formation and cell death.

FIGURE 2

Effects of pyroptosis on atherosclerosis. DAMPs induce the activation of NLRP3 or AIM2 inflammasome, which further activate caspase-dependent pyroptosis. ECs pyroptosis triggers monocyte recruitment into the intima in early atherogenesis. VSMC pyroptosis weakens fibrous caps and contributes to pathological instability in atherosclerosis. Macrophage pyroptosis promotes the formation of necrotic core and aggravates plaque instability in advanced atherosclerotic lesions.

FIGURE 3

Effects of ferroptosis on atherosclerosis. Ferroptosis and lipid peroxidation induce endothelial dysfunction, macrophage activation, and foam cell formation, contributing to the generation of atherosclerosis. ACSL4, LOXs, and hepcidin promote atherosclerosis by inducing lipid peroxidation and iron overload; in contrast, PDSS2 and ferrostatin-1 can inhibit ferroptosis and atherosclerosis by suppressing lipid peroxidation.

FIGURE 4

Association between autophagy and pyroptosis. Mitochondrial dysfunction and NOXs induce the massive production of ROS and stimulate the activation of inflammasome and caspase-1. LPS and oxidized mtDNA induce caspase-4/5/11 activation. Activated caspase-1/4/5/11 cleaves GSDMD, induces pyroptotic cell death, and promotes the release of IL-1β and IL-18. Mild oxidative stress triggers off autophagy, which inhibits inflammasome signaling and ROS production, thus protecting against pyroptosis.

FIGURE 5

Association between autophagy and ferroptosis. Several types of selective autophagy, including ferritinophagy, lipophagy, clockophagy, and CMA, promote lipid peroxidation and ferroptosis by promoting the degradation of ferritin, lipid droplets, ARNTL, and GPX4, respectively. Beclin-1 is phosphorylated by AMPK and then facilitates ferroptosis by binding and blocking the activity of system x_c ⁻. Autophagy inhibitors (e.g., 3-MA, Baf-A1) can prevent GSH depletion-dependent ferroptosis. STAT3-mediated CTSB expression and lysosomal cell death promote ferroptosis.