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Transcriptional downregulation of microRNA-19a by ROS production and NF-?B deactivation governs resistance to oxidative stress-initiated apoptosis.

ABSTRACT: Cell apoptosis is one of the main pathological alterations during oxidative stress (OS) injury. Previously, we corroborated that nuclear factor-?B (NF-?B) transactivation confers apoptosis resistance against OS in mammalian cells, yet the underlying mechanisms remain enigmatic. Here we report that microRNA-19a (miR-19a) transcriptionally regulated by reactive oxygen species (ROS) production and NF-?B deactivation prevents OS-initiated cell apoptosis through cylindromatosis (CYLD) repression. CYLD contributes to OS-initiated cell apoptosis, for which NF-?B deactivation is essential. MiR-19a directly represses CYLD via targeting 3' UTR of CYLD, thereby antagonizing OS-initiated apoptosis. CYLD repression by miR-19a restores the IKK? phosphorylation, RelA disassociation from I?B?, I?B? polyubiquitination and degradation, RelA recruitment at VEGF gene promoter as well as VEGF secretion in the context of OS. Either pharmacological deactivation of NF-?B or genetic upregulation of CYLD compromises the apoptosis-resistant phenotypes of miR-19a. Furthermore, miR-19a is transcriptionally downregulated upon OS in two distinct processes that require ROS production and NF-?B deactivation. VEGF potentiates the ability of miR-19a to activate NF-?B and render apoptosis resistance. Our findings underscore a putative mechanism whereby CYLD repression-mediated and NF-?B transactivation-dependent miR-19a regulatory feedback loop prevents cell apoptosis in response to OS microenvironment.

SUBMITTER: Hong J

PROVIDER: S-EPMC5642611 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Transcriptional downregulation of microRNA-19a by ROS production and NF-κB deactivation governs resistance to oxidative stress-initiated apoptosis.

Hong Jun J Wang Ying Y Hu Bang-Chuan BC Xu Liang L Liu Jing-Quan JQ Chen Min-Hua MH Wang Jin-Zhu JZ Han Fang F Zheng Yang Y Chen Xu X Li Qian Q Yang Xiang-Hong XH Sun Ren-Hua RH Mo Shi-Jing SJ

Oncotarget 20170812 41

Cell apoptosis is one of the main pathological alterations during oxidative stress (OS) injury. Previously, we corroborated that nuclear factor-κB (NF-κB) transactivation confers apoptosis resistance against OS in mammalian cells, yet the underlying mechanisms remain enigmatic. Here we report that microRNA-19a (miR-19a) transcriptionally regulated by reactive oxygen species (ROS) production and NF-κB deactivation prevents OS-initiated cell apoptosis through cylindromatosis (CYLD) repression. CYL ...[more]

PMID: 29050336

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Project description:Background: The anti-inflammatory and antioxidant capacity of carnosine (CAR) has been investigated in autoimmune diseases. The aim of this study was to evaluate the potential protective effects of oral CAR supplements to ameliorate type 2 diabetes mellitus (T2DM)-induced osteoarthritis (OA) in rats and its mechanism. Methods: Seventy male Sprague-Dawley rats were randomly divided into the control group (CG, n = 10) and the T2DM group (n = 60). A rat model of T2DM was established using a high fat diet and streptozotocin (30 mg/kg, i.p.). The 41 rats that developed T2DM were chosen and randomly divided into four groups: T2DM-induced OA group (OAG, n = 11), and the T2DM-induced OA with low, moderate, and high-doses of CAR for 8 weeks group (CAR-L, CAR-M, and CAR-H, n = 10). After 13 weeks, all rats were evaluated by enzyme-linked immunosorbent assay (ELISA), histology, immunohistochemistry, and western blotting. Fibroblast-like synoviocytes (FLSs) were obtained from the knee joints of all rats. The effects of CAR on the inflammatory response in interleukin (IL)-1β-stimulated FLSs under a high glucose environment were evaluated by real-time quantitative polymerase chain reaction, western blotting, flow cytometry, and immunofluorescence. Results: The results of ELISA (IL-1β and tumor necrosis factor-α), the histological evaluation (Mankin and OARSI score), western blotting [COL2A1, matrix metalloproteinase (MMP)-3, MMP-13, IL-1β, and nuclear factor-kappaB (NF-κB) p65], and immunohistochemistry (COL2A1, MMP-3, and MMP-13) indicated that oral CAR attenuated the development of T2DM-induced OA and suppressed the inflammatory response. Moreover, CAR alleviated MMP-3 and MMP-13 expression levels by decreasing reactive oxygen species content and suppressing nuclear translocation of NF-κB p65 on IL-1β-induced FLSs in a high glucose environment. Conclusion: These findings indicate that oral CAR had chondroprotective effects on T2DM-induced OA through the reactive oxygen species (ROS)/NF-κB pathway.

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Transcriptional downregulation of microRNA-19a by ROS production and NF-?B deactivation governs resistance to oxidative stress-initiated apoptosis.

Publications

Transcriptional downregulation of microRNA-19a by ROS production and NF-κB deactivation governs resistance to oxidative stress-initiated apoptosis.

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