Interplay between HSP90 and Nrf2 pathways in diabetes-associated atherosclerosis

Lázaro, Iolanda; Oguiza, Ainhoa; Recio, Carlota; López-Sanz, Laura; Bernal, Susana; Egido, Jesús; Gómez-Guerrero, Carmen

doi:10.1016/j.arteri.2016.10.003

Cited by 20 publications

(17 citation statements)

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“…Nrf2-mediated pathway is increasingly proposed as a way to prevent or treat disease. In preclinical models, pharmacological Nrf2 activators including 1,2-mercapto-3-sulfur ketone derivatives (oltipraz), isopropyl sulfur cyanogen compounds (sulforaphane), selenium-containing drugs (ebselen), natural products (resveratrol and curcumin) and phenolic compounds tBHQ, have been used as treatments for cancer, cardiovascular, metabolic and neurodegenerative diseases ( Jiang et al, 2010 ; Ma, 2013 ; Tan and de Haan, 2014 ; Tan et al, 2014 ; Chen et al, 2015 ; Lazaro et al, 2017 ). Several in vivo studies have described tBHQ cytoprotective actions under pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Nrf2 Activation Provides Atheroprotection in Diabetic Mice Through Concerted Upregulation of Antioxidant, Anti-inflammatory, and Autophagy Mechanisms

et al. 2018

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Interactive relationships between metabolism, inflammation, oxidative stress, and autophagy in the vascular system play a key role in the pathogenesis of diabetic cardiovascular disease. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a stress-sensitive guarantor of cellular homeostasis, which cytoprotective contributions extend beyond the antioxidant defense. We investigated the beneficial effects and underlying mechanisms of the Nrf2 inducer tert-butyl hydroquinone (tBHQ) on diabetes-driven atherosclerosis. In the experimental model of streptozotocin-induced diabetes in apolipoprotein E-deficient mice, treatment with tBHQ increased Nrf2 activity in macrophages and vascular smooth muscle cells within atherosclerotic lesions. Moreover, tBHQ significantly decreased the size, extension and lipid content of atheroma plaques, and attenuated inflammation by reducing lesional macrophages (total number and M1/M2 phenotype balance), foam cell size and chemokine expression. Atheroprotection was accompanied by both systemic and local antioxidant effects, characterized by lower levels of superoxide anion and oxidative DNA marker 8-hydroxy-2′-deoxyguanosine, reduced expression of NADPH oxidase subunits, and increased antioxidant capacity. Interestingly, tBHQ treatment upregulated the gene and protein expression of autophagy-related molecules and also enhanced autophagic flux in diabetic mouse aorta. In vitro, Nrf2 activation by tBHQ suppressed cytokine-induced expression of pro-inflammatory and oxidative stress genes, altered macrophage phenotypes, and promoted autophagic activity. Our results reinforce pharmacological Nrf2 activation as a promising atheroprotective approach in diabetes, according to the plethora of cytoprotective mechanisms involved in the resolution of inflammation and oxidative stress, and restoring autophagy.

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Section: Introductionmentioning

confidence: 99%

Nrf2 Activation Provides Atheroprotection in Diabetic Mice Through Concerted Upregulation of Antioxidant, Anti-inflammatory, and Autophagy Mechanisms

et al. 2018

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“…Heat-shock protein 90 (Hsp90) has been shown to be over-expressed in atherosclerotic plaque and plays a role in sustaining inflammatory mechanisms. 59 The inhibition of Hsp90 (using 17dimethylaminoethylamino-17-demethoxygeldanamycin) led to an increase in the activation of Nrf2, and an inhibition of pro-inflammatory NFjB in atherosclerotic plaques, resulting in reduced lesion size and decreased leucocytes and cytokines. 59 Furthermore, inhibition of Hsp90 led to increased induction of HO-1, SOD, catalase and autophagic machinery in the aortic tissue.…”

Section: Dh404mentioning

confidence: 99%

“…59 The inhibition of Hsp90 (using 17dimethylaminoethylamino-17-demethoxygeldanamycin) led to an increase in the activation of Nrf2, and an inhibition of pro-inflammatory NFjB in atherosclerotic plaques, resulting in reduced lesion size and decreased leucocytes and cytokines. 59 Furthermore, inhibition of Hsp90 led to increased induction of HO-1, SOD, catalase and autophagic machinery in the aortic tissue. Considering that Nrf2/Keap1 acts upstream of the pro-inflammatory IL-1b signal pathway, and that inhibition of Hsp90 also leads to an increase in Nrf2, the specific targeting of components of the antioxidant/ inflammatory pathway are valuable avenues of research for future pharmacological management of atherosclerosis.…”

Section: Dh404mentioning

confidence: 99%

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

et al. 2018

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Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

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“…The expression of COX-2 can promote the release and activation of matrix metalloproteinases,which play an important role in the migration of macrophages.Low density lipoprotein stimulates monocyte chemotaxis through the cox-dependent pathway.In general, Cox-2 expression induces prostaglandin production through activation of chemotaxis, induction of vascular permeability, cascade propagation of inflammatory cytokines, and stimulation of smooth muscle cell migration and proliferation,et al, thus promoting the formation and development of atherosclerosis [44] .HSP90AA1 is a subtype of the heat shock protein HSP90, and the overexpression of HSP90 in atherosclerotic plaques plays an important role in the maintenance of inflammation, which is related to the activation of nuclear factor-κB (NF-κB) pathway. HSP90 folds and activates IκB kinase,which phosphorylates and induces the degradation of the proteasome inhibitor protein IκBα, so that the nuclear factor-κB p65 subunit enters the nucleus, promoting the inflammatory response and promoting the transcription of oxidative genes [45] .The RELA gene encodes Transcription factor p65, a subunit of the transcription factor family NF-κB, which is a key regulator of eukaryotic inflammatory responses.Previous studies have shown that NF-κB is closely related to the formation and development of atherosclerosis,which induces the expression of adhesion proteins, monocyte chemotactic protein, IL-1βand other proinflammatory molecules in vascular endothelial cells to promote vascular inflammation [46] .The post-translational modification of RelA / p65 can finely regulate the transcriptional activation of NF-κB and play an important role in the occurrence and development of inflammatory response and diseases related to inflammatory response [47] .Furthermore, many previous studies have shown that other targets are closely related to the pathogenesis of atherosclerosis. For example, Interleukin-6, Interleukin-1βand other pro-inflammatory factors are involved in the formation and development of atherosclerosis [48][49] ,and the effects of matrix metalloproteinases such as MMP-1, MMP-3, and MMP-9 are closely related to the instability of atherosclerotic plaques [50] .All these previous studies provided certain theoretical support for our study.…”

Section: Figure7hljdd-key Active Ingredients-key Targets-pathway Netmentioning

confidence: 99%

Network Pharmacological Analysis of Huanglian Jiedu Decoction for Anti- Atherosclerosis

Wu¹,

Jiang²,

Huang³

et al. 2020

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Objective: We aimed to predict the possible active components,key targets and pathways of Huanglian Jiedu Decoction(HLJDD) for anti-atherosclerosis. Methods: The TCMSP database was searched to obtain the active components and targets of HLJDD, the GeneCards and OMIM databases were searched to obtain related targets of atherosclerosis, and we obtain the intersection targets of them, which are the potential targets of HLJDD for anti-atherosclerosis.Application of Cytoscape 3.6.0 software to build a herbal-active ingredient-potential target regulation network.We perform protein-protein interaction(PPI) network analysis of potential targets through STRING 11.0 database and obtain the key targets,and the results of PPI network of key targets were visualized by Cytoscape3.6.0 software. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the key targets were performed using STRING11.0 database, and we finally constructed the possible pharmacological network of HLJDD for anti-atherosclerosis .Results: We finally obtained 14 key active ingredients of HLJDD, 65 key targets of anti-atherosclerosis, and 14 key active ingredients corresponded to 52 of these targets. These targets are mainly involved in biological processes such as reaction to organic substance, reaction to chemical stimulation,etc.They mainly involved in biological signaling pathways such as pathways in cancer,IL-17 signaling pathway,etc. Conclusion: HLJDD may act on 52 key targets such as PTGS2, HSP90AA1 and RELA through 14 key active ingredients, and influence the signaling pathways including fluid shear stress and atherosclerosis,PI3K-Akt signaling pathway,IL-17 signaling pathway,AGE-RAGE signaling pathway in diabetic complications,TNF signaling pathway,etc.Thus, it may play an anti-atherosclerosis role by inhibiting inflammatory reaction, oxidative stress and improving hemodynamics,etc.

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Interplay between HSP90 and Nrf2 pathways in diabetes-associated atherosclerosis

Cited by 20 publications

References 48 publications

Nrf2 Activation Provides Atheroprotection in Diabetic Mice Through Concerted Upregulation of Antioxidant, Anti-inflammatory, and Autophagy Mechanisms

Nrf2 Activation Provides Atheroprotection in Diabetic Mice Through Concerted Upregulation of Antioxidant, Anti-inflammatory, and Autophagy Mechanisms

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

Network Pharmacological Analysis of Huanglian Jiedu Decoction for Anti- Atherosclerosis

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