The vicious circle of UHRF1 down‐regulation and KEAP1/NRF2/HO‐1 pathway impairment promotes oxidative stress‐induced endothelial cell apoptosis in diabetes

Abstract

Background Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin‐like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress‐induced endothelial cell (EC) apoptosis in diabetes. Methods Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual‐luciferase reporter assay, methylation‐specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. Results UHRF1 expression levels were significantly decreased in endothelial colony‐forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch‐like ECH‐associated protein 1 (KEAP1)/nuclear factor erythroid 2‐related factor 2 (NRF2)/haeme oxygenase‐1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down‐regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. Conclusion Diabetes‐induced oxidative stress can mediate down‐regulation of UHRF1, which enhances ROS production by regulating KEAP1/p‐NRF2 pathway through histone acetylation and might also form a self‐perpetuating feedback loop with KEAP1/p‐NRF2 to further promote oxidative stress‐induced apoptosis of ECs in diabetes.

atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers

“…Our finding that H 2 O 2 exposure synergistically enhances the small liver phenotype in hUHRF1 larvae indicates that UHRF1 overexpression may have high levels of ROS, which then activates Atm to prevents further accumulation of ROS. Recent studies suggest that downregulation of UHRF1 in cancer cells generates oxidative stress [ 64 , 65 ], and it is possible that the high levels of UHRF1 overexpression in this zebrafish model and in precancer cells exerts a dominant negative effect to suppress anti-oxidant defenses. Our findings point to Atm as a key factor that responds to UHRF1 overexpression and suggests the paradoxical function of Atm in pre-cancerous hepatocytes to sustain liver expansion, providing sufficient hepatic function to support survival.…”

Advanced multifunctional hydrogels for diabetic foot ulcer healing: Active substances and biological functions

“…However, excessive ROS can induce oxidative stress and thus hinder wound healing by causing protein modification, lipid peroxidation, DNA damage, and finally cell apoptosis 30 . Due to the hyperglycemic environment, DFU wounds show a high level of ROS and superoxide produced mainly by mitochondrial electron transport chain, which further promote oxidative stress injury and induce the production of advanced glycosylation end products (AGEs) 31,32 . Meanwhile, the uncoupling of nitric oxide synthase leads to the reduced production of nitric oxide, which also leads to chronic inflammation in diabetic wounds 33,34 .…”

“… 30 Due to the hyperglycemic environment, DFU wounds show a high level of ROS and superoxide produced mainly by mitochondrial electron transport chain, which further promote oxidative stress injury and induce the production of advanced glycosylation end products (AGEs). 31 , 32 Meanwhile, the uncoupling of nitric oxide synthase leads to the reduced production of nitric oxide, which also leads to chronic inflammation in diabetic wounds. 33 , 34 In conclusion, high ROS delay the inflammatory process, hinder cell proliferation, and obstruct remodeling during the four stages of wound healing, including hemostasis, inflammation, proliferation, and maturation.…”

Targeting Signalling Pathways in Chronic Wound Healing

“…Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), miR-181b-5p and Keap1 have been investigated as potential targets for promoting Nrf2 signalling. UHRF1 is an epigenetic modifier that modulates DNA methylation [ 111 ]. UHRF1 is a positive regulator of Nrf [ 111 ].…”