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.
Highlights
Atherosclerosis is a chronic lipid‐driven inflammatory disease that can cause life‐threatening complications, such as acute myocardialQingqing Xiao, Xinyu Che, and Bin Cai contributed to this work.infarct, stroke and aortic aneurysm.[1]
We found that autophagy could inhibit mac‐ rophage apoptosis and improve the stability of vulnerable plaques
We verified that activation of autophagy inhibited cell apoptosis, via improving macrophage mitochondrial dysfunction and inhibiting MAPK‐NF‐κB signalling pathway
Summary
Atherosclerosis is a chronic lipid‐driven inflammatory disease that can cause life‐threatening complications, such as acute myocardial. Mitochondrial dysfunction participates in a series of dis‐ eases,[16,17] such as acute renal injury,[18] neurodegeneration,[19] myocardial ischaemia/reperfusion injury[20] and heart failure.[21] Increased opening of mitochondrial permeability transition pore (MPTP) results in mitochondrial dysfunction, which includes mi‐ tochondrial membrane potential (MMP) loss, cytochrome c loss from the intermembrane space, excessive reactive oxygen species (ROS) generation and mitochondrial fission.[22] Recent data suggest that mitochondrial dysfunction plays a crucial role in macrophage death in advanced lesion.[23,24] cholesterol loading of mouse peritoneal macrophages induces cells apoptosis by damaging mi‐ tochondria.[25] Autophagy is the main way to degrade impaired mi‐ tochondria. Our findings may suggest the vasoprotection of autophagy against devel‐ opment of vulnerable plaques and provide key implications for the efficacy of autophagy‐targeted treatments for vulnerable plaques
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call