Role of Nitric Oxide and CCAAT/Enhancer-Binding Protein Transcription Factor in Statin-Dependent Induction of Heme Oxygenase-1 in Mouse Macrophages

Mouawad, Charbel; Mrad, May F.; Al‐Hariri, Moustafa; Soussi, Hiba Zouheir; Hamade, Eva; Alam, Jawed; Habib, Aı̈da

doi:10.1371/journal.pone.0064092

Cited by 7 publications

(5 citation statements)

References 45 publications

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“…We have previously shown that statins inhibits COX-2, a proinflammatory enzyme in monocytes in a Rac and NF-κB–dependent manner [21]. In addition statins have been shown to induce HO-1 expression and to inhibit the production of IL-6 and TNF-α in macrophages stimulated with LPS [16, 18, 37].…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1—Dependent anti-inflammatory effects of atorvastatin in zymosan-injected subcutaneous air pouch in mice

et al. 2019

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Statins exert pleiotropic and beneficial anti-inflammatory and antioxidant effects. We have previously reported that macrophages treated with statins increased the expression of heme oxygenase-1 (HO-1), an inducible anti-inflammatory and cytoprotective stress protein, responsible for the degradation of heme. In the present study, we investigated the effects of atorvastatin on inflammation in mice and analyzed its mechanism of action in vivo . Air pouches were established in 8 week-old female C57BL/6J mice. Atorvastatin (5 mg/kg, i.p.) and/or tin protoporphyrin IX (SnPPIX), a heme oxygenase inhibitor (12 mg/kg, i.p.), were administered for 10 days. Zymosan, a cell wall component of Saccharomyces cerevisiae, was injected in the air pouch to trigger inflammation. Cell number and levels of inflammatory markers were determined in exudates collected from the pouch 24 hours post zymosan injection by flow cytometry, ELISA and quantitative PCR. Analysis of the mice treated with atorvastatin alone displayed increased expression of HO-1, arginase-1, C-type lectin domain containing 7A, and mannose receptor C-type 1 in the cells of the exudate of the air pouch. Flow cytometry analysis revealed an increase in monocyte/macrophage cells expressing HO-1 and in leukocytes expressing MRC-1 in response to atorvastatin. Mice treated with atorvastatin showed a significant reduction in cell influx in response to zymosan, and in the expression of proinflammatory cytokines and chemokines such as interleukin-1α, monocyte chemoattractant protein-1 and prostaglandin E 2 . Co-treatment of mice with atorvastatin and tin protoporphyrin IX (SnPPIX), an inhibitor of heme oxygenase, reversed the inhibitory effect of statin on cell influx and proinflammatory markers, suggesting a protective role of HO-1. Flow cytometry analysis of air pouch cell contents revealed prevalence of neutrophils and to a lesser extent of monocytes/macrophages with no significant effect of atorvastatin treatment on the modification of their relative proportion. These findings identify HO-1 as a target for the therapeutic actions of atorvastatin and highlight its potential role as an in vivo anti-inflammatory agent.

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Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1—Dependent anti-inflammatory effects of atorvastatin in zymosan-injected subcutaneous air pouch in mice

et al. 2019

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“…These authors observed that treatment of the cells with NO donor nitroprusside (3 mM) for 8 h upregulated HO-1 levels in control cells to a higher extent than in Pin1 deficient cells and argued that Nrf2/ARE-mediated transcriptional activity is negatively controlled by Pin1 in fibroblasts [137]. However, the expression of HO-1 is controlled by both Nrf2 and AP-1 via partially overlapping AREs and TPA-responsive elements in the gene promotor [138], and Mouawad et al [139] showed that NO-dependent expression of HO-1 is controlled by transcription factors C/EBPβ and AP-1 in macrophages [139]. Therefore, we suggest the possibility that NO-activated AP-1 could induce HO-1 gene expression more efficiently in the absence of Pin1-mediated Nrf2 nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

Stress Activated MAP Kinases and Cyclin-Dependent Kinase 5 Mediate Nuclear Translocation of Nrf2 via Hsp90α-Pin1-Dynein Motor Transport Machinery

2023

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Non-lethal low levels of oxidative stress leads to rapid activation of the transcription factor nuclear factor-E2-related factor 2 (Nrf2), which upregulates the expression of genes important for detoxification, glutathione synthesis, and defense against oxidative damage. Stress-activated MAP kinases p38, ERK, and JNK cooperate in the efficient nuclear accumulation of Nrf2 in a cell-type-dependent manner. Activation of p38 induces membrane trafficking of a glutathione sensor neutral sphingomyelinase 2, which generates ceramide upon depletion of cellular glutathione. We previously proposed that caveolin-1 in lipid rafts provides a signaling hub for the phosphorylation of Nrf2 by ceramide-activated PKCζ and casein kinase 2 to stabilize Nrf2 and mask a nuclear export signal. We further propose a mechanism of facilitated Nrf2 nuclear translocation by ERK and JNK. ERK and JNK phosphorylation of Nrf2 induces the association of prolyl cis/trans isomerase Pin1, which specifically recognizes phosphorylated serine or threonine immediately preceding a proline residue. Pin1-induced structural changes allow importin-α5 to associate with Nrf2. Pin1 is a co-chaperone of Hsp90α and mediates the association of the Nrf2-Pin1-Hsp90α complex with the dynein motor complex, which is involved in transporting the signaling complex to the nucleus along microtubules. In addition to ERK and JNK, cyclin-dependent kinase 5 could phosphorylate Nrf2 and mediate the transport of Nrf2 to the nucleus via the Pin1-Hsp90α system. Some other ERK target proteins, such as pyruvate kinase M2 and hypoxia-inducible transcription factor-1, are also transported to the nucleus via the Pin1-Hsp90α system to modulate gene expression and energy metabolism. Notably, as malignant tumors often express enhanced Pin1-Hsp90α signaling pathways, this provides a potential therapeutic target for tumors.

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“…Based on the findings of these studies, S100A12 expression was transcriptionally up-regulated by CCAAT/enhancer-binding protein and activator protein. Since statins reportedly promote expression of other genes by activating these transcription factors 33,34) , further studies are needed to explore underlying mechanisms for atorvastatinmediated reduction of serum S100A12 levels.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation

Komatsu

Ayaori

Uto‐Kondo

et al. 2022

JAT

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Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. Methods:We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using 18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n 15) or one receiving atorvastatin (10mg/day, n 16) for 12weeks. 18 F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function.Results: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%). 18 F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of 18 F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery.Conclusions: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.C-reactive protein (CRP) levels are a good predictor for incidence of cardiovascular diseases (CVD) 2) . A number of clinical trials have shown that CVD events are reduced by treatment with statins (HMG-CoA

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Role of Nitric Oxide and CCAAT/Enhancer-Binding Protein Transcription Factor in Statin-Dependent Induction of Heme Oxygenase-1 in Mouse Macrophages

Cited by 7 publications

References 45 publications

Heme oxygenase-1—Dependent anti-inflammatory effects of atorvastatin in zymosan-injected subcutaneous air pouch in mice

Heme oxygenase-1—Dependent anti-inflammatory effects of atorvastatin in zymosan-injected subcutaneous air pouch in mice

Stress Activated MAP Kinases and Cyclin-Dependent Kinase 5 Mediate Nuclear Translocation of Nrf2 via Hsp90α-Pin1-Dynein Motor Transport Machinery

Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation

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