The Beneficial Role of Nrf2 in the Endothelial Dysfunction of Atherosclerosis

Huang, Zixia; Wu, Mingyue; Zeng, Lijin; Wang, Deming

doi:10.1155/2022/4287711

Cited by 9 publications

(6 citation statements)

References 80 publications

(80 reference statements)

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“…The Nrf2-dependent antioxidant response is a well-known protective mechanism against cardiovascular diseases and insults, including myocardial infarction [49], aortic stenosis [50], streptozotocininduced cardiac toxicity [51], myocardial ischemia reperfusion injury [52], diabetic cardiomyopathy [53], and atherosclerosis [54]. Likewise, several studies reported that during septic cardiomyopathy, Nrf2 activity protects heart function via multiple mechanisms [55][56][57].…”

Section: Discussionmentioning

confidence: 99%

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Zhu¹,

Dai²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3 -/- ) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

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Section: Discussionmentioning

confidence: 99%

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Zhu¹,

Dai²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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“…In the process of ferroptosis, almost all genes that regulate ferroptosis are related to Nrf2 regulation, which mainly includes genes that regulate glutathione (GSH) synthesis, system xc–induced cysteine supply, glutathione reductase, and GPX4, the activity of which is crucial for the activity of GPX4. NADPH regeneration, including glucose-6-phosphate dehydrogenase, phosphoglycerate dehydrogenase, and malic enzyme, and iron regulation, including iron excretion and storage, heme synthesis (degradation), and ferritin synthesis [ 109 , 110 ]. Nrf2 physically binds to the mitochondria and can track and respond to changes in mitochondrial function.…”

Section: Disorders Of Iron Metabolism Leading To Hfmentioning

confidence: 99%

Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure

Zhang,

Luo,

et al. 2024

Eur J Med Res

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The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.

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“…As a critical anti‐oxidative stress pathway, the Nrf2/ARE signaling pathway plays a pivotal role in combating atherosclerosis (AS) through its antioxidative properties. This is primarily evident in the protection of vascular endothelial integrity, reduction of lipid accumulation, and inhibition of inflammation (Huang, Wu, et al, 2022; Zhuang et al, 2021).…”

Section: Nrf2/are Signaling Pathwaymentioning

confidence: 99%

Modulation of atherosclerosis‐related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives

Liu,

Guo,

Zhang

2024

Phytotherapy Research

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Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt), NF‐E2‐related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator‐activated receptor (PPAR), nucleotide oligo‐structural domain‐like receptor thermoprotein structural domain‐associated protein 3 (NLRP3), silencing information regulator 2‐associated enzyme 1 (Sirt1), nuclear transcription factor‐κB (NF‐κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor‐β (TGF‐β), and Janus kinase‐signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high‐intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.

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The Beneficial Role of Nrf2 in the Endothelial Dysfunction of Atherosclerosis

Cited by 9 publications

References 80 publications

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure

Modulation of atherosclerosis‐related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives

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