Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway

Zhang, Huojun; Zhou, Ling; Zhou, Yuhao; Wang, Lingling; Jiang, Wanling; Lü, Ling; Yue, Shuang; Zheng, Pengdou; Liu, Huiguo

doi:10.1016/j.lfs.2021.119963

Cited by 29 publications

(7 citation statements)

References 61 publications

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“…NRF2 binds to the antioxidant response element to transcriptionally activate downstream genes encoding Glutathione S-transferase, Aldehyde dehydrogenase, CAT, Heme oxygenase 1, and Thioredoxin 30 . However, most reports emphasize the role of increased NOX levels and activity in CIH-induced adverse vascular outcomes 24 , 31 , and few studies have linked NRF2 regulation to CIH-induced endothelial dysfunction, although some studies similarly revealed that CIH inhibited NRF2 expression 4 , 32 . In the present study, we demonstrated that NRF2 downregulation in CIH-treated mouse aorta or in CIH-treated endothelial cells results in excess superoxide production and impaired endothelial function, an effect rescued by the NRF2 agonist, Oltipraz, or by the ROS scavengers, Tempol or Tiron and DETCA.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular vesicle-derived miR-144 as a novel mechanism for chronic intermittent hypoxia-induced endothelial dysfunction

Zhang¹,

Lü²,

Wang³

et al. 2022

Theranostics

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Rationale: Extracellular vesicles (EVs) play a significant role in cell-cell communication. However, whether and how extracellular vesicles are involved in chronic intermittent hypoxia-induced endothelial dysfunction is unknown. Methods: Comparative transcriptomics analysis and miRNA screening were used to identify the possible pathways or target molecules mediating chronic intermittent hypoxia-induced endothelial function. Serum- or erythrocyte-derived EVs were isolated through ultracentrifugation plus filtration. After in vitro or in vivo treatment with EVs, aortic rings were treated with dihydroethidium staining for superoxidative anion measurement or mounted with wire myography to measure isometric forces. Immunoblotting and qPCR were used for evaluating the molecular mechanism mediating EV miR-144-induced endothelial function under intermittent hypoxia. Results: We revealed a previously undefined importance of circulating extracellular vesicles in regulating endothelial function via delivery of miR-144 to endothelial cells, reducing nuclear factor erythroid 2-related factor 2 expression. Additionally, we identified that erythrocytes were the primary cellular source of miR-144-enriched serum-derived extracellular vesicles and that erythrocyte-derived extracellular vesicles were largely responsible for chronic intermittent hypoxia-impaired endothelial function. Furthermore, silencing of miR-144 by anti-miR-144 confirmed its essential role in endothelial dysfunction elicited by erythrocyte-derived extracellular vesicles from chronic intermittent hypoxia-exposed C57BL/6 mice. Conclusion: The results expand the scope of blood-borne substances involved in vascular homeostasis and suggest that anti-miR-144-loaded extracellular vesicles may represent a promising therapeutic approach against obstructive sleep apnea or chronic intermittent hypoxia-associated endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

“…Anti-oxidative transcription factor NRF2 preserves endothelial function and prevents Ang II-induced hypertension 3 . It has been reported that CIH induced myocardial injury by inhibiting NRF2 protein expression 4 , but whether NRF2 mediates CIH-related endothelial dysfunction and hypertension is still obscure.…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicle-derived miR-144 as a novel mechanism for chronic intermittent hypoxia-induced endothelial dysfunction

Zhang¹,

Lü²,

Wang³

et al. 2022

Theranostics

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“…GSK’872 (5 mg/kg/day, i.p.) or vehicle was administrated to mice (10 mice in each group) right after the last injection of STZ for a total of 2 months [ 30 ]. The plasmid DNA containing MISSION ® shRNA for MLKL ( p shMLKL, 60 µg, Sigma, Oakville, ON, Canada) or an empty plasmid was injected into Akita mice (male, 2 months old, 6 mice in each group) through tail veins with GenJet™ Plus DNA in vivo transfection reagent following the manufacturer’s instructions (SignaGen ® Laboratories, Frederick, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes

Cao

Ding

et al. 2022

Cardiovasc Diabetol

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Background Cardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes. Methods Type 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed. Results We showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes. Conclusions We have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.

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“…It was reported that inhibition of RIPK3 by GSK'872 treatment significantly reduced phosphorylation of MLKL and cytosolic Ca 2+ concentrations in retinal cells in vitro following elevated hydrostatic pressure 72 , 165 . In addition, the anti-necroptotic effect of GSK'872 has been indicated in osteoclastogenesis and non-alcoholic fatty liver disease in vitro and in vivo 166 , 167 . However, the in vivo retinal neuroprotective efficiency of GSK'872 still needs to be confirmed.…”

Section: Therapeutic Options To Target Necroptosis In Retinamentioning

confidence: 99%

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases

Zhang¹,

Hu²,

Zhao³

et al. 2023

Int. J. Biol. Sci.

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The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis -traditionally thought of as uncontrolled cell death -in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.

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Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway

Cited by 29 publications

References 61 publications

Extracellular vesicle-derived miR-144 as a novel mechanism for chronic intermittent hypoxia-induced endothelial dysfunction

Extracellular vesicle-derived miR-144 as a novel mechanism for chronic intermittent hypoxia-induced endothelial dysfunction

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases

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