HO-1 alleviates cholesterol-induced oxidative stress through activation of Nrf2/ERK and inhibition of PI3K/AKT pathways in endothelial cells

Jin, Xiaojuan; Xu, Zhongwei; Fan, Rong; Wang, Chengyan; Ji, Wenjie; Ma, Yongqiang; Cai, Wei; Zhang, Yan; Yang, Ning; Zou, Shuang; Zhou, Xin; Li, Yuming

doi:10.3892/mmr.2017.6962

Cited by 24 publications

(15 citation statements)

References 39 publications

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“…On the contrary, recently published data pointed out that upregulation of cholesterol caused oxidative damage in vascular EC and increased the expression of HO-1 via the activation of Nrf2 and the MAPK/ERK signaling pathway. Therefore, overexpression of HO-1 may alleviate oxidative damage [ 43 ]. Following this mechanism, simvastatin-induced decrease in total and LDL cholesterol levels of our AAA patients may partially explain the weak effects of simvastatin on HO-1 and Nrf2.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Piechota-Polańczyk

Kopacz

Klóska

et al. 2018

Oxidative Medicine and Cellular Longevity

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Heme oxygenase-1 (HO-1), encoded by HMOX1 gene and regulated by Nrf2 transcription factor, is a cytoprotective enzyme. Its deficiency may exacerbate abdominal aortic aneurysm (AAA) development, which is also often associated with hyperlipidemia. Beneficial effects of statins, the broadly used antilipidemic drugs, were attributed to modulation of Nrf2/HO-1 axis. However, the effect of statins on Nrf2/HO-1 pathway in patients with AAA has not been studied yet. We analyzed AAA tissue from patients treated with simvastatin (N = 28) or without statins (N = 14). Simvastatin treatment increased HO-1 protein level in AAA, both in endothelial cells (ECs) and in smooth muscle cells (SMCs), but increased Nrf2 localization was restricted only to vasa vasorum. Nrf2 target genes HMOX1, NQO1, and GCLM expression remained unchanged in AAA. In vitro studies showed that simvastatin raises HO-1 protein level slightly in ECs and to much higher extent in SMCs, which is not related to Nrf2/ARE activation, although HMOX1 expression is upregulated by simvastatin in both cell types. In conclusion, simvastatin-induced modulation of HO-1 level in ECs and SMCs in vitro is not related to Nrf2/ARE activity. Likewise, divergent HO-1 and Nrf2 localization together with stable expression of Nrf2 target genes, including HMOX1, in AAA tissue denotes Nrf2 independency.

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Section: Discussionmentioning

confidence: 99%

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Piechota-Polańczyk

Kopacz

Klóska

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…p38 is a critical member of mitogen-activated protein kinases (MAPKs), playing a role in inducing the activation of antioxidant response element (ARE) which is a component of intracellular antioxidant defense system [ 10 ]. The activation of ARE signaling, further triggers the expressions and synthesis of the downstream anti-oxidant enzymes such as heme oxygenase (HO1) [ 11 ]. The activation of p38/Nrf2 signaling could increase the anti-oxidant potential which suppresses the apoptosis and inflammation responses [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…The activation of ARE signaling, further triggers the expressions and synthesis of the downstream anti-oxidant enzymes such as heme oxygenase (HO1) [ 11 ]. The activation of p38/Nrf2 signaling could increase the anti-oxidant potential which suppresses the apoptosis and inflammation responses [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Attenuates Cognitive Deficits of Traumatic Brain Injury by Activating p38 Signaling in the Brain

et al. 2018

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BackgroundTraumatic brain injury (TBI) is characterized by cognitive deficits, which was associated with brain oxidative stress and apoptosis. Resveratrol (RSV) is an anti-apoptotic and anti-oxidative. This study aimed to investigate neuroprotective effects and involved molecular mechanisms in TBI.Material/MethodsRSV and p38 inhibitor were administrated to TBI rats. Cognitive deficits were evaluated by Morris water maze assay. Reactive oxygen species (ROS) and apoptosis were detected in rat brains by fluorescent staining. Western blotting was used to assess the phosphorylation of p38 and the expression levels of Nrf2, HO1, and activated caspase-3.ResultsRSV administration attenuated cognitive deficits of TBI rats. The ROS generation and apoptosis in the brain of TBI rats were suppressed by RSV treatment. Moreover, RSV treatment recovered activation of p38/Nrf2/HO1 signaling pathway. The co-administration of p38 inhibitor impaired RSV’s attenuating effects on cognitive deficits, brain apoptosis, and ROS generation.ConclusionsRSV attenuated cognitive deficits of TBI by inhibiting oxidative stress-mediated apoptosis via targeting p38/Nrf2 signaling.

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“…Nε-Carboxymethyl-Lysine (the key active component of AGEs, CML) signi cantly decreased the phosphorylation of PI3K/AKT signaling and restoration of PI3K/AKT signaling in cell apoptosis. The results showed RAGE induced foam cell apoptosis in diabetic atherosclerosis by inhibiting the PI3K/AKT pathway [53].…”

Section: Discussionmentioning

confidence: 95%

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

Yao

Zhang

Yang

et al. 2020

Preprint

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Background: Both experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics. Methods: In this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin-eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis. Results: After PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change >1.3 and P-value <0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell aggregation. The cellular signaling pathways involved in glycosylation may be AGE-RAGE signaling pathway.Conclusion: The present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE-RAGE signal pathway in glycation biology.

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HO-1 alleviates cholesterol-induced oxidative stress through activation of Nrf2/ERK and inhibition of PI3K/AKT pathways in endothelial cells

Cited by 24 publications

References 39 publications

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Resveratrol Attenuates Cognitive Deficits of Traumatic Brain Injury by Activating p38 Signaling in the Brain

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

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