4-Hydroxy-2-Nonenal Promotes Cardiomyocyte Necroptosis via Stabilizing Receptor-Interacting Serine/Threonine-Protein Kinase 1

Zhai, Xiaoxuan; Wang, Wenjun; Sun, Shukun; Yu, Han; Li, Jiaxin; Cao, Shengchuan; Li, Ruochuan; Xu, Tonghui; Yuan, Qiuhuan; Wang, Jiali; Wei, Shujian; Chen, Yuguo

doi:10.3389/fcell.2021.721795

Cited by 14 publications

(11 citation statements)

References 37 publications

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“…Therefore we also measured 4-HNE protein adduction using western blot. Consistent with the data reported, we observed an increase in 4-HNE adducted protein following H/R injury [ 20 , 21 ]. Pre-treatment with BMX-001 significantly reduced 4-HNE adducted protein ( Figure 3 C).…”

Section: Resultssupporting

confidence: 93%

Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress

Sharma

Subedi

et al. 2023

IJMS

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Myocardial ischemia-reperfusion injury (I/R) causes damage to cardiomyocytes through oxidative stress and apoptosis. We investigated the cardioprotective effects of MnTnBuOE-2-PyP5+ (BMX-001), a superoxide dismutase mimic, in an in vitro model of I/R injury in H9c2 cardiomyocytes. We found that BMX-001 protected against hypoxia/reoxygenation (H/R)-induced oxidative stress, as evident by a significant reduction in intracellular and mitochondrial superoxide levels. BMX-001 pre-treatment also reduced H/R-induced cardiomyocyte apoptosis, as marked by a reduction in TUNEL-positive cells. We further demonstrated that BMX-001 pre-treatment significantly improved mitochondrial function, particularly O2 consumption, in mouse adult cardiomyocytes subjected to H/R. BMX-001 treatment also attenuated cardiolipin peroxidation, 4-hydroxynonenal (4-HNE) level, and 4-HNE adducted proteins following H/R injury. Finally, the pre-treatment with BMX-001 improved cell viability and lactate dehydrogenase (LDH) activity in H9c2 cells following H/R injury. Our findings suggest that BMX-001 has therapeutic potential as a cardioprotective agent against oxidative stress-induced H/R damage in H9c2 cardiomyocytes.

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Section: Resultssupporting

confidence: 93%

Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress

Sharma

Subedi

et al. 2023

IJMS

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“…Our previous study showed that the clearance of 4-HNE protected against MI/R injury by restraining necroptosis. [20] In this study, we further verified that 4-HNE provoked myocyte ferroptosis in MI/R insults. Cardiac-specific knockout of ALDH2, the key metabolic enzyme of 4-HNE, aggravated 4-HNE accumulation and ferroptosis, whereas the activation of ALDH2 exerted opposite effects.…”

Section: Discussionsupporting

confidence: 75%

Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury

et al. 2023

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Despite the development of advanced technologies for interventional coronary reperfusion after myocardial infarction, a substantial number of patients experience high mortality due to myocardial ischemia‐reperfusion (MI/R) injury. An in‐depth understanding of the mechanisms underlying MI/R injury can provide crucial strategies for mitigating myocardial damage and improving patient survival. Here, it is discovered that the 4‐hydroxy‐2‐nonenal (4‐HNE) accumulates during MI/R, accompanied by high rates of myocardial ferroptosis. The loss‐of‐function of aldehyde dehydrogenase 2 (ALDH2), which dissipates 4‐HNE, aggravates myocardial ferroptosis, whereas the activation of ALDH2 mitigates ferroptosis. Mechanistically, 4‐HNE targets glutathione peroxidase 4 (GPX4) for K48‐linked polyubiquitin‐related degradation, which 4‐HNE‐GPX4 axis commits to myocyte ferroptosis and forms a positive feedback circuit. 4‐HNE blocks the interaction between GPX4 and ovarian tumor (OTU) deubiquitinase 5 (OTUD5) by directly carbonylating their cysteine residues at C93 of GPX4 and C247 of OTUD5, identifying OTUD5 as the novel deubiquitinase for GPX4. Consequently, the elevation of OTUD5 deubiquitinates and stabilizes GPX4 to reverse 4‐HNE‐induced ferroptosis and alleviate MI/R injury. The data unravel the mechanism of 4‐HNE in GPX4‐dependent ferroptosis and identify OTUD5 as a novel therapeutic target for the treatment of MI/R injury.

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“…Apoptosis is mainly responsible for cell death in mild acute pancreatitis while necrosis accounts for most of the cell death in SAP ( Bhatia, 2004a ). Necrosis has traditionally been viewed as a form of passive cell death, although RIP-driven necrosis was recently identified and was commonly termed as necroptosis ( Zhai et al, 2021 ). Necroptosis is activated by ligand binding to death receptors such as tumor necrosis factor-alpha receptor 1 (TNFR1) ( Chan et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis

Sun

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored.Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death.Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist.Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.

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4-Hydroxy-2-Nonenal Promotes Cardiomyocyte Necroptosis via Stabilizing Receptor-Interacting Serine/Threonine-Protein Kinase 1

Cited by 14 publications

References 37 publications

Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress

Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress

Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis

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