AIM2 accelerates the atherosclerotic plaque progressions in ApoE−/− mice
Introduction
Atherosclerosis (AS) is a complex pathological condition in vascular disease [1,2], leading to many chronic and acute ailments, such as unstable angina pectoris, hypertension, myocardial infarction and sudden coronary death. The progression of AS is characterized by the accumulation of lipids in vessel walls, increased inflammation, changes in artery structure and cell death [1,[3], [4], [5]]. Hyperlipidemia is a major risk factor for atherosclerosis with low-density lipoprotein (LDL) levels playing a pivotal role [6].
Apoptosis and pyroptosis are two forms of programmed cell death. Although a variety of studies have indicated that apoptosis is the primary form of programmed cell death, cell death in atherosclerosis is more complex. Pyroptosis is a novel form of programmed cell death and is uniquely dependent on GSDMD [7]. While caspase-1 is not involved in apoptosis, since caspase-1-deficient cells still respond to apoptotic signals [8], it can promote the activation and release of GSDMD-N, a cytokine that plays an important role in pyroptosis [9]. Pyroptosis progression is characterized by the loss of cell membrane potential and DNA fragmentation, the latter of which can be detected by positive terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining. Pyroptosis was initially discovered in immunological cells with bacterial or viral infections, but a recent study showed that ox-LDL can promote pyroptosis [10]. Previous studies of pyroptosis focused on endothelial cells and macrophages [6,11]; however, the role of ox-LDL in promoting pyroptosis in VSMCs has not been thoroughly elucidated to date.
Absent in melanoma 2 (AIM2) is a cytosolic DNA sensor, the activation of which leads to inflammasome formation in macrophages [[12], [13], [14]]. AIM2 belongs to the HIN200 family of hematopoietic interferon (IFN)-inducible genes and plays an important role in host defense against DNA viruses and certain cytosolic bacteria [15,16]. Previous studies focused on the role of AIM2 in inflammation involving the innate immune system [[17], [18], [19], [20]]. Alternatively, other studies found that AIM2 promotes pyroptosis in tumor cells [21,22]. AIM2 has also been shown to play a role in the progression of abdominal aortic aneurysm [23]. Despite intense interest in this DNA sensor, the role of AIM2 in atherosclerosis has not been thoroughly elucidated to date.
We hypothesized that AIM2 promotes pyroptosis and ICAM-1 expression in VSMCs and that this effect could affect the progression of atherosclerosis. In this study, we investigated the mechanism and effect of pyroptosis and ICAM-1 in VSMCs.
Section snippets
Reagents
Mice were purchased from HFK Bioscience Company (Beijing, China), and ox-LDL was purchased from Yiyuan Biotechnology (Guangzhou, China). Rabbit anti-mouse primary antibodies against AIM2, caspase-1, GSDMD-N, and α-SMA were obtained from Abcam (Shanghai, China). Rabbit anti-mouse primaries antibodies against ASC and AIM2 were purchased from Cell Signaling Technology (Shanghai, China). A mouse anti-GAPDH antibody was purchased from Bioss (Beijing, China). Lentivirus AIM2 and AIM2-shRNA were
High-fat diet increases LDL levels in ApoE−/−mice
LDL levels in mice fed a high-fat diet were increased compared to mice fed a chow diet (Fig. 1A). AIM2 overexpression or inhibition had no effect on the LDL level.
ICAM-1 are dependent on AIM2 expression in ApoE−/− mice
RT-PCR showed that AIM2 expression was increased in lvAIM2 and decreased in shRNA group mice. AIM2 expression was also increased in mice that were fed a high-fat diet compared to the control group (Fig. 1B). Next, the role of AIM2 in regulating inflammasome activation in response to a high-fat diet was examined. ICAM-1 increased in
Discussion
The progression of atherosclerosis contributes to a variety of chronic diseases, including hypertension, coronary heart disease and sudden cardiac death [1,25]. Recent studies have shown that a high-fat diet promotes the progression of atherosclerosis due to the accumulation of lipids in the vessel wall, which promotes inflammation, changes in artery structure and cell death [1,[3], [4], [5]]. Cell death in the vascular wall, particularly in VSMCs, can initiate plaque formation and aggravate
Conflicts of interest
All authors declare no financial or commercial conflicts of interest.
Funding
This project was supported by the National Natural Science Foundation of China (No. 81670325 and No. 81370325).
Acknowledgments
The authors thank Yun Zhang for his help in editing the manuscript.
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