Role of ALK5/SMAD2/3 signaling in the regulation of NOX expression in cerebral ischemia/reperfusion injury

Lou, Zheng; Wang, Aiping; Duan, Xingguang; Hu, Guo‐Huang; Zuo, Meiling; Yang, Zhong‐Bao

doi:10.3892/etm.2018.6377

Cited by 5 publications

(6 citation statements)

References 31 publications

(47 reference statements)

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“…B, ROS production measured by flow cytometry in the indicated groups, n = 3. 40 In line with previous studies, we observed in this study that the ALK5/Smad2/3 pathway was activated, as evidenced by elevated levels of ALK and p-Smad2/3 which induced the upregulation of Nox4 in I/R injury, both in vivo and in vitro. C, Western blot analysis for the protein expression of NLRP3, ASC, Caspase-1, and IL-1β and bar graph showed quantification, n = 3.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, the relationship between ALK5/Smad2/3 signaling pathway and the occurrence of oxidative stress was identified by Lou et al who revealed that ALK5/Smad2/3 pathway was associated with ROS generation through targeting Nox4/Nox2 activity in cerebral I/R injury. 40 In line with previous studies, we observed in this study that the ALK5/Smad2/3 pathway was activated, as evidenced by elevated levels of ALK and p-Smad2/3 which induced the upregulation of Nox4 in I/R injury, both in vivo and in vitro. In addition, knockdown of ALK5 with si-RNA downregulated ALK5 and p-Smad2/3 levels, ultimately leading to a remarkable decrease in the levels of Nox4 upon H/R injury stimuli, further demonstrating that Nox4 was modulated by the ALK5/Smad2/3 pathway.…”

Section: Discussionsupporting

confidence: 92%

“…Recently, emerging evidence had demonstrated that activation of the ALK5/Smad2/3 pathway was responsible for neurological recovery through interacting with Gadd45b in cerebral I/R injury, indicating that the ALK5/Smad2/3 pathway might be involved in the progression of I/R injury. Furthermore, the relationship between ALK5/Smad2/3 signaling pathway and the occurrence of oxidative stress was identified by Lou et al who revealed that ALK5/Smad2/3 pathway was associated with ROS generation through targeting Nox4/Nox2 activity in cerebral I/R injury …”

Section: Discussionmentioning

confidence: 99%

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Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model

et al. 2019

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contributed equally to this work.Abbreviations: AKI, acute kidney injury; ALK5, activin receptor-like kinase; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; BUN, blood urea nitrogen; Cr, creatinine; EZH2, enhancer of zeste homolog 2; FLICA, fluorescent-labeled inhibitors of caspases; H/R, hypoxia/reoxygenation; H3K27me3, histone H3 lysine 27 trimethylation; HK-2, human renal proximal tubular epithelial cell line; I/R, ischemia/reperfusion; IL-1β, interleukin-1beta; LDH, lactate dehydrogenase; MDA, malondialdehyde; NAC, N-acetyl-cysteine; NADPH, nicotinamide adenine dinucleotide phosphate; NLRP3, NOD-like receptor family pyrin domain-containing protein 3; Nox4, NADPH oxidase 4; PRC2, polycomb repressive complex 2; ROS, reactive oxygen species; RT-PCR, real-time polymerase chain reaction; siRNA, small interfering RNA; SOD, superoxide dismutase; TGF-β, transforming growth factor beta; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. AbstractEnhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a crucial role in several kidney disease models. However, its role in renal ischemia/reperfusion (I/R) injury still remains unclear. In this study, we found that EZH2 was positively related to renal I/R injury and inhibition of EZH2 with DZNeP alleviated I/R injury and blocked the activation of oxidative stress and pyroptosis in vivo. Similarly, inhibition of EZH2 with either DZNeP or si-RNA also exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and pyroptosis in vitro. Moreover, further study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine (NAC) suppressed pyroptosis in human renal proximal tubular epithelial cell line cells exposed to H/R stimulation. Furthermore, Nox4, which was positively related to the generation of ROS, was upregulated during H/R process, while it could be reversed by EZH2 inhibition. Consistently, Nox4-mediated ROS generation was attenuated upon inhibition of EZH2 with DZNeP or si-RNA. Additionally, the transcriptional activity of Nox4 was enhanced by the activation of ALK5/Smad2/3 signaling pathway, which was abolished by ALK5 knockdown in vitro. Finally, EZH2 inhibition blocked H/R and I/R-activated ALK5/Smad2/3 pathway and also resulted in an obvious decrease in the transcriptional activity and protein expression levels of Nox4. In conclusion, our results proved that EZH2 inhibition alleviated renal pyroptosis by blocking Nox4-dependent ROS generation through ALK5/Smad2/3 signaling pathway, indicating that EZH2 could be a potential therapeutic target for renal I/R injury. K E Y W O R D Senhancer of zeste homolog 2, ischemia-reperfusion injury, oxidative stress, pyroptosis, Nox4, reactive oxygen species 836 | LIU et aL.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model

et al. 2019

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“…Nox4-induced oxidative stress is a pathological feature of cerebral hypoxia-ischemia 53,54 and Rictor/mTorc2 deficiency has been shown to aggravate HI-induced injury in various models 55,56 . Based on this knowledge, we aimed to verify the involvement of the Parp3-mTorc2 axis in vivo in normal mice and in response to HI.…”

Section: Enhanced Nox4-induced Ros In Parp3-deficient Cells Cause Incmentioning

confidence: 99%

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

et al. 2020

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Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia.

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“…However, as soon as angiogenesis and subsequent blood perfusion, ischemic reperfusion injury occurs 7,8. It means that oxidative stress occurs in the ischemia tissue and injuries random skin flaps, accompanied with cell apoptosis 9,10. Previous studies have demonstrated that promoting angiogenesis, and suppressing oxidative stress and apoptosis can enhance random skin flap survival.…”

Section: Introductionmentioning

confidence: 99%

<p>Therapeutic potential of pravastatin for random skin flaps necrosis: involvement of promoting angiogenesis and inhibiting apoptosis and oxidative stress</p>

Lin¹,

Jia²,

Wang³

et al. 2019

DDDT

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Background: Random skin flap is frequently used in plastic and reconstructive surgery, but its distal part often occurs ischemia and necrosis. Pravastatin (Prava) with bioactivities of pro-angiogenesis, anti-apoptosis and anti-oxidative stress, may be beneficial for flap survival. Materials and methods: A modified McFarlane flap model was performed in Sprague-Dawley rats. The animals were divided into the Control and Prava groups and treated as follows: the Prava group was injected intraperitoneally with 2 mg/kg Prava for consecutive 7 days, and the Control group received an equal volume of vehicle daily. On day 7, the necrosis skin flaps were observed, while visualization of blood flow below the tissue surface was performed by Laser Doppler blood flow imaging (LDBFI). Then animals were euthanized, and levels of angiogenesis, apoptosis and oxidative stress were analyzed. Results: Prava decreased necrosis and edema of skin flaps compared with the Control group, with more blood flow in the flap under LDBFI. Prava treatment increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins (superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase), and decreased the expression of apoptotic factors (BAX, CYC, Caspase3). In addition, malondialdehyde content was reduced, and glutathione level and SOD activity were increased in the skin flaps after treatment with Prava. Conclusion: Prava promotes survival of random skin flap through induction of angiogenesis, and inhibition of apoptosis and oxidative stress.

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Role of ALK5/SMAD2/3 signaling in the regulation of NOX expression in cerebral ischemia/reperfusion injury

Cited by 5 publications

References 31 publications

Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model

Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

<p>Therapeutic potential of pravastatin for random skin flaps necrosis: involvement of promoting angiogenesis and inhibiting apoptosis and oxidative stress</p>

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