AIM2 regulates vascular smooth muscle cell migration in atherosclerosis

Pan, Jinyu; Lu, Lu; Wang, Xuyang; Liu, Dian; Tian, Jingjing; Liu, Hui; Zhang, Mingjun; Xu, Fengqin; An, Fengshuang

doi:10.1016/j.bbrc.2018.02.094

Cited by 30 publications

(23 citation statements)

References 35 publications

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“…In line with our results, Pan et al recently demonstrated that AIM2 promotes the progression of atherosclerotic plaques in ApoE −/− mice by increasing migration in vascular smooth muscle cells (VSMC) (41). By intravenous injection of a murine AIM2 lentivirus, shRNA-AIM2 lentivirus, and null lentivirus into ApoE −/− mice, the authors could show that the area of aortic atherosclerotic lesions was larger and the number of VSMC increased with elevated levels of AIM2.…”

Section: Discussionsupporting

confidence: 91%

AIM2 Stimulation Impairs Reendothelialization and Promotes the Development of Atherosclerosis in Mice

Lüsebrink

Goody

Lahrmann

et al. 2020

Front. Cardiovasc. Med.

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Background: Atherosclerosis has been shown to result from chronic inflammation caused by constitutive activation of the pattern recognition receptors (PRR), which are principle effectors of the innate immune system. PRR are present in the endosome or on the cellular membrane and can sense the aberrant release of nucleic acids, which is often a sign of acute or chronic cellular damage. Absent in melanoma 2 (AIM2) is a PRR that is expressed by vascular cells and specializes in detecting cytoplasmic double-stranded DNA (dsDNA). Activation of AIM2 leads eventually to activation of the inflammasome, but the role of AIM2 in vascular disease and atherosclerosis has not been well-studied. Therefore, in this study we took advantage of acute and chronic models of vascular injury to determine the biological role of AIM2 in atherogenesis. Methods and Results: We were able to induce significant release of proinflammatory cytokines in mice through the intravenous injection of a synthetic ligand for AIM2, double-stranded poly dA:dT. This cytokine release was shown to impair reendothelialization of the carotid artery and increase the number of circulating endothelial microparticles (EMP) after acute denudation, compared to treatment with vehicle. We saw an increase in the production of reactive oxygen species in the aorta, the number of circulating EMP, and, most interestingly, atherosclerotic plaque formation in apolipoprotein E-deficient (ApoE −/− ) mice when they received continual subcutaneous poly dA:dT, in contrast to vehicle-treated animals. Finally, treatment with poly dA:dT did not impair vascular reendothelialization in AIM2 −/− mice compared to vehicle controls in the carotid artery injury model. Conclusion: Overall, our data suggest that AIM2, as a known regulator of the inflammasome, is an active participant in atherogenesis, and highlight the importance of fully understanding the pathological mechanisms involved. It seems to be worth of further exploration as a therapeutic target, and future studies focusing on the effects of AIM2 activation as well as its pharmacological inhibition may reveal promising new therapeutic concepts for the treatment of atherosclerosis.

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Section: Discussionsupporting

confidence: 91%

AIM2 Stimulation Impairs Reendothelialization and Promotes the Development of Atherosclerosis in Mice

Lüsebrink

Goody

Lahrmann

et al. 2020

Front. Cardiovasc. Med.

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“…It has been reported that the TGF-β signaling pathway was an essential modulator in a vast array of cellular processes affiliated with AS (Thompson, Wilson, Wyllie, Wyllie, & Tannock, 2018). The TGF-β overexpression has been demonstrated to elevate neointimal hyperplasia, whereas deletion of TGF-β can inhibit neointimal growth (Pan et al, 2018). Another study showed that TGF-β signaling regulates vascular repair through modulating the endothelial cell (K. Wang, Lu, Liu, & Tao, 2018).…”

Section: -3p In Asmentioning

confidence: 99%

microRNA‐338‐3p promotes ox‐LDL‐induced endothelial cell injury through targeting BAMBI and activating TGF‐β/Smad pathway

Yin

Hou

Yang

2018

Journal Cellular Physiology

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microRNAs (miRNAs) have been revealed to participate in the pathological process of atherosclerosis (AS). However, the exact role of miR‐338‐3p, a target miRNA of BMP and activin membrane‐bound inhibitor (BAMBI), and its possible molecular mechanism in AS remain unidentified. In this study, we found that BAMBI was significantly decreased, whereas miR‐338‐3p increased in patients with AS and oxidized low‐density lipoprotein (ox‐LDL)‐induced HUVEC cells. Furthermore, overexpression of miR‐338‐3p significantly decreased cell viability and elevated cell apoptosis, whereas its inhibition significantly promoted cell viability and inhibited cell apoptosis in ox‐LDL‐induced HUVEC cells. Moreover, miR‐338‐3p overexpression increased TGF‐β/Smad pathway activation in ox‐LDL‐induced HUVEC cells. A dual‐luciferase reporter assay confirmed the direct interaction between miR‐338‐3p and the 3′‐untranslated region of BAMBI messenger RNA. Furthermore, the suppression of BAMBI ameliorated the effect of miR‐338‐3p inhibition against ox‐LDL‐induced HUVEC cell injury. In conclusion, our study thus suggests that miR‐338‐3p promoted ox‐LDL‐induced HUVEC cell injury by targeting BAMBI and activating the TGF‐β/Smad pathway, which may provide a novel and promising therapeutic target for AS.

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“…In addition, the AIM2 inflammasome is also well characterised in autoimmune and inflammatory diseases such as dermatitis and arthritis and cancers [34,35]. A role of AIM2 in atherosclerosis through regulation of vascular muscle cell migration and inflammation [36,37] was reported. To date, a direct role of AIM2 in metabolism has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance

et al. 2019

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Aims/hypothesis Absent in melanoma 2 (AIM2) is a cytosolic sensor for double-stranded DNA and a tumour suppressor. Binding of double-stranded DNA to AIM2 forms the AIM2 inflammasome, leading to activation of caspase-1 and production of IL-1β and IL-18. Although inflammasome-independent effects of AIM2 have been reported, its role in energy metabolism is unknown. We aimed to evaluate the effect of AIM2 in energy metabolism and glucose homeostasis. Methods Male and female whole body Aim2 knockout (Aim2 −/−) mice were used in the current study. Body weight, food intake, body composition, energy expenditure, fasting blood glucose levels, GTT and body temperature were measured at indicated time points. RNA sequencing was carried out on gonadal white adipose tissue (gWAT) in 14-month-old female mice. mRNA and protein levels in tissues were analysed by quantitative real-time PCR and immunoblot. Immune cell infiltration in gWAT was examined by flow cytometry. Stromal vascular fractions isolated from gWAT were used to investigate adipocyte differentiation. Results Male and female Aim2 −/− mice were obese compared with wild-type controls from 7 weeks of age until 51 weeks of age, with increased adiposity in both subcutaneous and visceral fat depots. While there were no differences in food intake, Aim2 −/− mice demonstrated decreased energy expenditure and impaired brown adipose tissue function compared with wild-type controls. Fasting glucose and insulin levels were elevated, and Aim2 −/− mice were glucose intolerant on intraperitoneal GTT. RNA sequencing revealed marked upregulation of the IFN-inducible gene Ifi202b, which encodes protein 202 (p202) and elevated inflammatory signalling in gWAT of Aim2 −/− mice. Increased infiltration of total and Ly6C low monocytes was noted at 8 weeks of age in gWAT, before the onset of obesity and insulin resistance. Ifi202b knockdown blocked adipogenesis in stromal vascular fractions and reduced inflammation in bone marrow-derived macrophages, demonstrating a key role of p202 in mediating the increased adipogenesis and inflammation in Aim2 −/− mice. Conclusions/interpretation These results demonstrate a fundamental role for AIM2 in energy metabolism, inflammation and insulin resistance. Our studies establish a novel link between the innate immunity proteins, AIM2 and p202, and metabolism.

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AIM2 regulates vascular smooth muscle cell migration in atherosclerosis

Cited by 30 publications

References 35 publications

AIM2 Stimulation Impairs Reendothelialization and Promotes the Development of Atherosclerosis in Mice

AIM2 Stimulation Impairs Reendothelialization and Promotes the Development of Atherosclerosis in Mice

microRNA‐338‐3p promotes ox‐LDL‐induced endothelial cell injury through targeting BAMBI and activating TGF‐β/Smad pathway

Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance

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