Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction

Zhang, Yi; Lv, Xuemei; Hu, Zizhong; Ye, Xiaojian; Zheng, Xinhua; Ding, Yibing; Xie, Ping

doi:10.1038/cddis.2017.308

Cited by 104 publications

(83 citation statements)

References 44 publications

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“…The second signalling pathway induces conformational changes in the NLRP3 inflammasome platform and activates caspase 1 to convert pro-IL-1β into the mature secreted form of IL-1β. The NLRP3 inhibitor MCC950 has been shown to inhibit highglucose-induced RMEC dysfunction, consistent with the promising clinical effects of an IL-1 receptor antagonist for the treatment of diabetic retinopathy [5].…”

Section: Introductionsupporting

confidence: 60%

“…Early clinical symptoms include retinal microvascular endothelial cell (RMEC) dysfunction and vascular dysfunction [3,4]. Emerging evidence indicates that high-glucose-induced para-inflammation, characterised by a chronic low level of inflammation and a disordered immune response, is involved in the onset and progression of RMEC damage [5,6]. The retinas from animal models of diabetes show inappropriate activation of the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, which is a molecular complex of NLRP3, apoptosisassociated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC) and procaspase 1 [7].…”

Section: Introductionmentioning

confidence: 99%

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Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

Wang

Xie

et al. 2018

Diabetologia

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Aims/hypothesis Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E 2 (PGE 2 ) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE 2 and its E-prostanoid receptor (EP 2 R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction. Methods In a streptozotocin (STZ)-induced rat model of diabetes, rats received intravitreal injection of PGE 2 , butaprost (a PGE 2 / EP 2 R agonist) or AH6809 (an EP 2 R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed. Results Intravitreal injection of PGE 2 and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE 2 -and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC), and activation of the EP 2 R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway. Conclusions/interpretation The PGE 2 /EP 2 R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment.

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Section: Introductionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

Wang

Xie

et al. 2018

Diabetologia

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“…It has also been reported in APP/PS1 mice, an AD model, that MCC950 suppresses inflammasome activation and IL‐1β production, stimulates Aβ phagocytosis in vitro , and reduces Aβ accumulation (Dempsey et al, ). With regard to the retina, MCC950 is capable of inhibiting NLRP3 inflammasome activation and apoptosis in human retinal endothelial cells (HRECs) under high‐glucose conditions, likely through downregulation of the Nek7–NLRP3 pathway (Zhang et al, ).…”

Section: Targeting Inflammasome Activation In Retinal Degenerative DImentioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.

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“…In particular, endothelial cells (EC) in the retinal vasculature are primary targets of glucose-induced damage in diabetic retinopathy (DR) (Fiori et al, 2018). Endothelial dysfunction (ED) is a characteristic feature of DR and is a key event in the early development and progression of the disease (Ao, Liu, Li, & Lu, 2019;Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs

et al. 2020

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Diabetic complications cause significant morbidity and mortality. Dysfunction of vascular endothelial cells (ECs), caused by oxidative stress, is a main mechanism of cellular damage. Oxidative stress accelerates EC senescence and DNA damage. In this study, we examined the role of mitochondrial sirtuins (SIRTs) in glucose‐induced oxidative stress, EC senescence, and their regulation by miRNAs. Human retinal microvascular endothelial cells (HRECs) were exposed to 5 mmol/L (normoglycemia; NG) or 25 mmol/L glucose (hyperglycemia; HG) with or without transfection of miRNA antagomirs (miRNA‐1, miRNA‐19b, and miRNA‐320; specific SIRT‐targeting miRNAs). Expressions of SIRT3, 4 and 5 and their targeting miRNAs were examined using qRT‐PCR and ELISAs were used to study SIRT proteins. Cellular senescence was investigated using senescence‐associated β‐gal stain; while, oxidative stress and mitochondrial alterations were examined using 8‐OHdG staining and cytochrome B expressions, respectively. A streptozotocin‐induced diabetic mouse model was also used and animal retinas and hearts were collected at 2 months of diabetes. In HRECs, HG downregulated the mRNAs of SIRTs, while SIRT‐targeting miRNAs were upregulated. ELISA analyses confirmed such downregulation of SIRTs at the protein level. HG additionally caused early senescence, endothelial‐to‐mesenchymal transition and oxidative DNA damage in ECs. These changes were prevented by the transfection of specific miRNA antagomirs and by resveratrol. Retinal and cardiac tissues from diabetic mice also showed similar reductions of mitochondrial SIRTs. Collectively, these findings demonstrate a novel mechanism in which mitochondrial SIRTs regulate glucose‐induced cellular aging through oxidative stress and how these SIRTs are regulated by specific miRNAs. Identifying such mechanisms may lead to the discovery of novel treatments for diabetic complications.

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Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction

Cited by 104 publications

References 44 publications

Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs

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