Effect of ferroptosis on chronic cerebral hypoperfusion in vascular dementia

Fu, Peijie; Chen, Yanghang; Wu, Moxin; Bao, Bing; Yin, Xiaoping; Chen, Zhiying; Zhang, Manqing

doi:10.1016/j.expneurol.2023.114538

Cited by 6 publications

(2 citation statements)

References 66 publications

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“…VD is becoming a major public health concern worldwide . Considerable evidence indicates a link between CCH and VD, although the causal relationship remains unclear. CCH triggers a cascade of molecular and cellular responses leading to BBB breakdown and neurodegeneration .…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of VCAM1 on Brain Endothelial Cells Drives Blood–Brain Barrier Impairment Following Chronic Cerebral Hypoperfusion

Zhang,

Shang,

et al. 2024

ACS Chem. Neurosci.

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Chronic cerebral hypoperfusion (CCH)-triggered blood−brain barrier (BBB) dysfunction is a core pathological change occurring in vascular dementia (VD). Despite the recent advances in the exploration of the structural basis of BBB impairment and the routes of entry of harmful compounds after a BBB leakage, the molecular mechanisms inducing BBB impairment remain largely unknown in terms of VD. Here, we employed a CCH-induced VD model and discovered increased vascular cell adhesion molecule 1 (VCAM1) expression on the brain endothelial cells (ECs). The expression of VCAM1 was directly correlated with the severity of BBB impairment. Moreover, the VCAM1 expression was associated with different regional white matter lesions. Furthermore, a compound that could block VCAM1 activation, K-7174, was also found to alleviate BBB leakage and protect the white matter integrity, whereas pharmacological manipulation of the BBB leakage did not affect the VCAM1 expression. Thus, our results demonstrated that VCAM1 is an important regulator that leads to BBB dysfunction following CCH. Blocking VCAM1mediated BBB impairment may thus offer a new strategy to treat CCH-related neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Increased Expression of VCAM1 on Brain Endothelial Cells Drives Blood–Brain Barrier Impairment Following Chronic Cerebral Hypoperfusion

Zhang,

Shang,

et al. 2024

ACS Chem. Neurosci.

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“…SLC7A11 maintains the production of GSH, a major endogenous antioxidant, through a series of reactions involving the exchange of extracellular cysteine with intracellular glutamate 46 . Inhibiting the SLC7A11 pathway stands out as a critical upstream mechanism for inducing ferroptosis 57 . The expression of GPX4 and SLC7A11 at both protein and RNA levels was investigated in RSL3-treated HUEVCs.…”

Section: Discussionmentioning

confidence: 99%

Kaempferol Rescues Vascular Endothelial Ferroptosis by Inhibiting Lipid Peroxidation

Wen,

Zhang,

Wang

et al. 2024

Biomed. Res. Ther.

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Introduction:The vascular endothelium plays a pivotal role in maintaining vascular function and physiological balance. The degradation and injury of endothelial cells are critical pathological events in the progression of vascular diseases, leading to cell death. One such cell death mechanism, ferroptosis, is an iron-dependent form of necrosis characterized by extensive lipid peroxidation-mediated membrane damage and the toxic effects of iron and lipid peroxidation. Kaempferol, a flavonoid, is celebrated for its antioxidant, anti-inflammatory, and anti-cancer properties. Despite these benefits, the impact of Kaempferol on endothelial cell ferroptosis and its potential therapeutic applications in vascular diseases have yet to be fully elucidated. Methods: Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Oxidative stress and lipid peroxidation were measured using Dihydroethidium (DHE) and C11-BODIPY 581/591, respectively. The protein and RNA levels of ferroptosis-associated molecules, including solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), were determined through Western blotting and real-time fluorescence quantitative polymerase chain reaction (qPCR). Results: Treatment with a glutathione peroxidase 4 inhibitor (RSL3) led to rapid cytotoxicity in human umbilical vein endothelial cells (HUVECs). Notably, Kaempferol demonstrated a significant protective effect against RSL3-induced ferroptosis in HUVECs. Kaempferol treatment reduced the accumulation of reactive oxygen species (ROS) and exhibited distinctive morphological changes associated with ferroptosis. Moreover, Kaempferol treatment resulted in the upregulation of SLC7A11 and GPX4 expression in HUVECs, highlighting its potent ability to mitigate ferroptosis among tested flavonoids. Conclusions: Kaempferol effectively inhibited RSL3-induced ferroptosis in HUVECs by modulating the expression of SLC7A11 and GPX4, thereby reducing lipid peroxidation. These findings underscore the therapeutic potential of Kaempferol in the treatment of vascular diseases, paving the way for its application in clinical settings.

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Physical and social environmental enrichment alleviate ferroptosis and inflammation with inhibition of TLR4/MyD88/p38MAPK pathway in chronic cerebral hypoperfusion rats

Fan,

Zhang,

Luo

et al. 2024

Brain Research Bulletin

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Effect of ferroptosis on chronic cerebral hypoperfusion in vascular dementia

Cited by 6 publications

References 66 publications

Increased Expression of VCAM1 on Brain Endothelial Cells Drives Blood–Brain Barrier Impairment Following Chronic Cerebral Hypoperfusion

Increased Expression of VCAM1 on Brain Endothelial Cells Drives Blood–Brain Barrier Impairment Following Chronic Cerebral Hypoperfusion

Kaempferol Rescues Vascular Endothelial Ferroptosis by Inhibiting Lipid Peroxidation

Physical and social environmental enrichment alleviate ferroptosis and inflammation with inhibition of TLR4/MyD88/p38MAPK pathway in chronic cerebral hypoperfusion rats

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