AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model

Wang, Xuyang; Pan, Jinyu; Liu, Hui; Zhang, Mingjun; Liu, Dian; Lu, Lu; Tian, Jingjing; Liu, Ming; Jin, Tao; An, Fengshuang

doi:10.1016/j.lfs.2019.02.035

Cited by 66 publications

(49 citation statements)

References 41 publications

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“…Downregulation of CMKLR1 suppressed cardiac cell death in DCM rats. Although apoptosis and necrosis are the forms of cell death that are normally detected in DCM patients (Chowdhry et al, 2007;D'Arcy, 2019;Ge et al, 2019;Qi et al, 2020) recent studie have shown that other types of cell death, such as pyroptosis, are also found in DCM (Wang X. et al, 2019). Pyroptosis is a type of programmed cell death that is commonly induced by caspase-1 activation, and is characterized by pore formation on the plasma membrane, cell swelling, nuclear DNA damage, and release of intracellular inflammatory content (Liu et al, 2016;Lacey et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to apoptosis, cells undergoing pyroptosis incur DNA damage and become TUNEL-positive; and as with necrosis, pyroptosis exhibits membrane pore formation, release of proinflammatory cytoplasmic content, and cell rupture (Liu et al, 2016). EthD-III, a type of cell membrane-impermeant nucleic acid dye, stains pyroptotic cells by entering through the membrane pores, but does not stain cells with intact membranes (Pan et al, 2018;Wang X. et al, 2019). The permeability of pyroptotic cell membranes can also be determined through the release of the cytoplasmic enzyme lactose dehydrogenase (LDH) (Ding et al, 2019;Gu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…The permeability of pyroptotic cell membranes can also be determined through the release of the cytoplasmic enzyme lactose dehydrogenase (LDH) (Ding et al, 2019;Gu et al, 2019). Recent studies showed that pyroptosis also occurs in cardiomyocytes (Pan et al, 2018;Meng et al, 2019;Wang X. et al, 2019). In our previous study, we showed that NLRP3 inflammasomeinduced caspase-1 activation promotes cardiomyocyte pyroptosis in DCM.…”

Section: Introductionmentioning

confidence: 99%

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Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

et al. 2020

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Chemerin and its receptor CMKLR1 (a G-protein-coupled receptor) are inducers of inflammation, and play an important role in diabetic cardiomyopathy (DCM). In this study, we investigated the role of the chemerin/CMKLR1 axis in mediating inflammation and cell death in DCM. Sprague-Dawley rats, treated with a high-fat diet and low-dose of streptozotocin, were used as a DCM model. CMKLR1 expression was knocked down by siRNA (CMKLR1-siRNA) to evaluate the role of CMKLR1 in DCM. Chemerintreated H9c2 cells were used to investigate the factors acting downstream of the chemerin/CMKLR1 axis. LDH release and EthD-III staining were used to measure the ratio of cell death in vitro. CMKLR1-siRNA and siRNA against nucleotide-binding oligomerization domain-like receptors 3 (NLRP3-siRNA) were used to explore the mechanism underlying chemerin-induced inflammation and cell death. The results showed that the expression of chemerin, CMKLR1, NLRP3, pro-caspase-1, activated caspase-1, and mature IL-1β was increased in the DCM model rat. Myocardium of DCM model rats exhibited fibrosis, hypertrophy, a disorganized ultrastructure, and impaired function. Pyroptosis was observed in vivo and in vitro. Silencing of CMKLR1 in vivo attenuated the expression of NLRP3 and activated caspase-1 and IL-1β. CMKLR1-siRNA treatment attenuated cardiac inflammation, fibrosis, hypertrophy, and pyroptosis, and improved cardiac function in vivo. Silencing of either CMKLR1 or NLRP3 suppressed the levels of activated caspase-1, IL-1β, and pyroptosis; however, silencing of both CMKLR1 and NLRP3 further decreased the levels of mature IL-1β and pyroptosis. Overall, the results showed that the chemerin/CMKLR1 axis contributed to the development of DCM and that the NLRP3 inflammasome mediated the chemerin/CMLR1-induced inflammation and pyroptosis. These data indicate that silencing of the CMKLR1 gene might exert a protective effect against DCM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

et al. 2020

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“…Furthermore, the detrimental role of AIM2 on cardiovascular health has been indicated by another study which showed increased AIM2 expression in the heart tissue of mice subjected to streptozotocin (STZ)‐induced diabetes. Also, when H9C2 cardiac myoblasts are treated with higher concentration of glucose, the AIM2 expression and pyroptotic cell death increased; whereas, the silencing of AIM2 alleviated GSDMD activity and pyroptosis in these cells . However, how AIM2 gets activated in the cardiac myoblasts during hyperglycemia is a question of discussion.…”

Section: Role Of Aim2 In Sterile Inflammatory Diseasesmentioning

confidence: 99%

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

2019

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AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.Keywords: AIM2 r cell death r gasdermin r inflammasome r pyroptosis

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“…87 Similarly, the silencing of Aim2 with siRNA in a diabetic rat model ameliorated diabetes-associated cardiomyopathy. 88 The AIM2 inflammasome has also been suggested to play a role in postoperative ileus. 89…”

Section: Autoimmune and Sterile Inflammatory Diseasesmentioning

confidence: 99%

AIM2 in health and disease: Inflammasome and beyond

Kumari

Russo

Shivcharan

et al. 2020

Immunological Reviews

121

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Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline‐encoded innate immune receptors detect microbial DNA in various compartments of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor‐dependent type I IFN synthesis followed by JAK/STAT‐dependent interferon‐stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase‐1. Caspase‐1 cleaves and activates the pro‐inflammatory cytokines such as IL‐1β and IL‐18 and a pore‐forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome‐dependent and inflammasome‐independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.

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AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model

Cited by 66 publications

References 41 publications

Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

AIM2 in health and disease: Inflammasome and beyond

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