Macrophage autophagy regulates mitochondria‐mediated apoptosis and inhibits necrotic core formation in vulnerable plaques

Abstract

The vulnerable plaque is a key distinguishing feature of atherosclerotic lesions that can cause acute atherothrombotic vascular disease. This study was designed to explore the effect of autophagy on mitochondria‐mediated macrophage apoptosis and vulnerable plaques. Here, we generated the mouse model of vulnerable carotid plaque in ApoE−/− mice. Application of ApoE−/− mice with rapamycin (an autophagy inducer) inhibited necrotic core formation in vulnerable plaques by decreasing macrophage apoptosis. However, 3‐methyladenine (an autophagy inhibitor) promoted plaque vulnerability through deteriorating these indexes. To further explore the mechanism of autophagy on macrophage apoptosis, we used macrophage apoptosis model in vitro and found that 7‐ketocholesterol (7‐KC, one of the primary oxysterols in oxLDL) caused macrophage apoptosis with concomitant impairment of mitochondria, characterized by the impairment of mitochondrial ultrastructure, cytochrome c release, mitochondrial potential dissipation, mitochondrial fragmentation, excessive ROS generation and both caspase‐9 and caspase‐3 activation. Interestingly, such mitochondrial apoptotic responses were ameliorated by autophagy activator, but exacerbated by autophagy inhibitor. Finally, we found that MAPK‐NF‐κB signalling pathway was involved in autophagy modulation of 7‐KC–induced macrophage apoptosis. So, we provide strong evidence for the potential therapeutic benefit of macrophage autophagy in regulating mitochondria‐mediated apoptosis and inhibiting necrotic core formation in vulnerable plaques.

Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases

“…Furthermore, an increase in ROS generation has also been reported to ultimately prevent the fusion of lysosomes with autophagosomes and could therefore contribute to increase LC3-II level [ 95 ]. Altogether, our present results demonstrate that 7KC also induces a type of death by oxiapoptophagy on N2a cells and confirm in nerve cells that the type of autophagy activated by 7KC is survival autophagy, such as that described on 7KC-treated cells of the vascular wall (macrophages, smooth muscle cells) [ 43 , 98 , 99 ], as well as on 7β-hydroxycholesterol-treated rat C6 glioma cells [ 88 ]. Our data bring new evidence that 7KC-induced oxiapoptophagy is independent of the cell type and of the species considered, since it can be observed on monocytic cells [ 43 ], human bone marrow mesenchymal stem cells [ 46 ], murine glial and microglial cells [ 40 , 45 ] and also murine neuronal N2a cells.…”

IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway

“…Much evidence has accrued that the apoptosis of macrophages can influence the stability of atherosclerotic plaques (25,47). Macrophage apoptosis intensifies the formation of plaque necrotic cores, causes thinning of the fibrous cap, and ultimately leads to PR (48)(49)(50). Therefore, we speculate that IRGM/Irgm1 contributes to plaque vulnerability by promoting macrophage apoptosis in advanced atherosclerotic plaques.…”

Strongylocentrotusnudos Egg Polysaccharide induces autophagy and apoptosis in leukaemia cells by regulating mitochondrial function

“…Cells were incubated with 50, 100 or 200 μg/mL of SEP for 24h, followed by 10 μmol/L DCFH‐DA treatment for 30 minutes. Fluorescence intensity was evaluated using a fluorescence microplate reader (Thermo Fisher Scientific, Waltham, MA, USA) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm 16 …”

“…The excitation and emission wavelengths of the JC‐1 monomer and polymer were 490 nm/530 nm and 525 nm/590 nm, respectively. Mitochondrial membrane potential changes were calculated by the red to green fluorescence ratio 16 …”

“…Fluorescence intensity was evaluated using a fluorescence microplate reader (Thermo Fisher Scientific, Waltham, MA, USA) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. 16…”