Novel role of Egr-1 in nicotine-related neointimal formation

Vázquez-Padrón, Roberto I.; Mateu, Dania; Rodriguez-Menocal, Luis; Wei, Yange; Webster, Keith A.; Pham, Si M.

doi:10.1093/cvr/cvq213

Cited by 31 publications

(22 citation statements)

References 37 publications

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“…Therefore, transcriptional activation of Egr1 and its downstream targets is pivotal in cellular events following oxidant stress. It has been reported that ERK1/2 is translocated to the nucleus of vascular smooth muscle cells after nicotine exposure to target the transcription factor ELK1, which, in turn, upregulates the expression of EGR1 as a key player in the progression of atherosclerosis . Therefore, in the present study we evaluated Egr1 expression in mice to investigate the role of the ERK/ELK1 pathway in the action of pravastatin in preventing the development of atherosclerosis.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, it has been reported that activation of the ROS/ERK/ELK1 pathway upregulates early growth response 1 (EGR1), a major mediator of the cellular stress response that is induced by stress, injury, mitogens and cytokines . Furthermore, EGR1 has been consistently implicated in vascular pathology as a key regulator of cellular proliferative and apoptotic pathways, so EGR1 is a known atherogenic transcription factor . Thus, the ERK1/2/ELK1 pathway may be an important target in the treatment of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

“…19,20 Furthermore, EGR1 has been consistently implicated in vascular pathology as a key regulator of cellular proliferative and apoptotic pathways, 21 so EGR1 is a known atherogenic transcription factor. 22 Thus, the ERK1/2/ELK1 pathway may be an important target in the treatment of atherosclerosis.…”

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confidence: 99%

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Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway

Zhou

2017

Clin Exp Pharma Physio

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Oxidative stress plays an important role in atherosclerosis, a vascular disease with high morbidity and mortality. The ETS domain-containing protein ELK1 is an oxidative stress-sensitive factor modulated by the extracellular signal-regulated kinase (ERK) 1/2 pathway. However, the role of ELK1 in the prevention of atherosclerosis by pravastatin remains unclear. In the present study, male apolipoprotein E-knockout (apoE ) mice fed a diet containing 1.25% cholesterol (w/w) were divided into two groups, one treated with pravastatin (80 mg/kg, 2-2.4 mg/mouse per day) for 8 weeks and the other not. Male C57BL/6J mice fed with a normal diet were used as a control group. Human umbilical vein endothelial cells (HUVEC) were cultured and treated with pravastatin (10 μmol/L) for 18 hours before testing for the presence or absence of 100 μmol/L H O (24 hours). Examination of pathological sections from mice aortas revealed that pravastatin treatment almost prevented atherosclerotic plaque formation. Pravastatin also inhibited increases in serum and aortic levels of oxidized low-density lipoprotein and aortic malondialdehyde levels and decreases in aortic reduced glutathione, and the activities of superoxide dismutase, catalase and glutathione peroxidase. H O -induced increases in reactive oxygen species in HUVECs were reversed by pravastatin by 48%. Pravastatin blocked the phosphorylation of ELK1 and ERK1/2 proteins and reduced mRNA levels of early growth response 1, a known atherogenic transcription factor upregulated by the ROS/ERK/ELK1 pathway, in mice. In conclusion, pravastatin attenuates the action of ELK1 induced by oxidative stress to prevent atherosclerosis, which is dependent partly on modulation of ERK1/2 signalling.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway

Zhou

2017

Clin Exp Pharma Physio

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“…RNAi Consortium lentiviruses (Thermo Scientific Open Biosystems, Huntsville, AL) carrying short hairpin (sh)RNAs to knock down murine SCF were initially tested in VSMCs. Cells were cultured and puromycin selected as previously described (45). The selected functional sequence for in vivo knockdown was 5=-TTACAAGCGAAATGAGAGCCG-3= (clone identifier: TRCN0000067868).…”

Section: Methodsmentioning

confidence: 99%

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

Skartsis

Martinez

Duque

et al. 2014

American Journal of Physiology-Renal Physiology

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Skartsis N, Martinez L, Duque JC, Tabbara M, Velazquez OC, Asif A, Andreopoulos F, Salman LH, Vazquez-Padron RI. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae. Am J Physiol Renal Physiol 307: F1095-F1104, 2014. First published September 3, 2014 doi:10.1152/ajprenal.00292.2014.-Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-Kit W/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. arteriovenous fistula; hemodialysis; neointima THE ARTERIOVENOUS (A-V) fistula is the preferred type of vascular access for hemodialysis patients (29). It achieves higher patency rates, has fewer complications than synthetic grafts (12,29,31), and has a lower risk of infections than central venous catheters (17,29). Despite its advantages, A-V fistulae frequently fail to mature or become dysfunctional after successful dialysis sessions, and this occurs primarily due to the development of neointimal hyperplasia (NIH) within the A-V fistula circuit (2, 5, 39). Stenosed A-V fistulae can sometimes be salvaged through angioplasty or surgical interventions, but these attempts often result in restenosis or additional complications (32). Therefore, there is an unmet medical need for treatments that prevent NIH and improve A-V fistula function. To this end, it is necessary to better define the factors underlying the pathological remodeling of the A-V fistula wall.A-V fistula maturation is a dynamic vascular process with multiple factors contributing to the development of NIH. These include vein configuration (22) In the present study, we investigated the role of c-Kit in the pathological remodeling of A-V fistulae. We show that activation of the c-Kit signaling pathway in adventitial and neointimal cells precedes arteri...

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“…Its involvement has been reported in cancer metastasis [12], inﬂammation [13], atherosclerosis [14], and ischemic injury [15]. Moreover, recent studies revealed that abnormal expression and function of Egr-1 are linked to animal models of fibrosis, as well as human fibrotic disorders, including idiopathic pulmonary fibrosis and scleroderma [16,17,18].…”

Section: Introductionmentioning

confidence: 99%

Egr-1 Mediates Chronic Hypoxia-Induced Renal Interstitial Fibrosis via the PKC/ERK Pathway

et al. 2014

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Background: Chronic hypoxia-induced epithelial-to-mesenchymal transition (EMT) is a crucial process in renal fibrogenesis. Egr-1, as a transcription factor, has been proven to be important in promoting EMT. However, whether it functions in hypoxia-induced renal tubular EMT has not been fully elucidated. Methods: Egr-1 were detected at mRNA and protein levels by qPCR and Western blot analysis respectively after renal epithelial cells were subjected to hypoxia treatment. Meanwhile, EMT phenotype was also observed through identification of relevant EMT-specific markers. siRNA was used to knock down Egr-1 expression and subsequent changes were observed. Specific PKC and MAPK/ERK inhibitors were employed to determine the molecular signaling pathway involved in Egr-1-mediated EMT phenotype. In vivo assays using rat remnant kidney model were used to validate the in vitro results. Furthermore, Egr-1 expression was examined in the samples of CKD patients with the clinical relevance revealed. Results: Hypoxia treatment enhanced the mRNA and protein levels of Egr-1 in HK-2 cells, which was accompanied by a reduced expression of the epithelial marker E-cadherin and an enhanced expression of the mesenchymal marker Fsp-1. Downregulation of Egr-1 with siRNA reversed hypoxia-induced EMT. Using the specific inhibitors to protein kinase C (calphostin C) or MAPK/ERK (PD98059), we identified that hypoxia induced Egr-1 expression through the PKC/ERK pathway. In addition, the upregulation of Egr-1 raised endogenous Snail levels, and the downregulation of Snail inhibited Egr-1-mediated EMT in HK-2 cells. Through in vivo assays using rat remnant kidney and CKD patients' kidney tissues, we found that Egr-1 and Snail were overexpressed in tubular epithelial cells with EMT. Conclusion: Egr-1 may be an important regulator of the development of renal tubular EMT induced by hypoxia through the PKC/ERK pathway and the activation of Snail. Targeting Egr-1 expression or activity might be a novel therapeutic strategy to control renal fibrosis.

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Novel role of Egr-1 in nicotine-related neointimal formation

Abstract: Nicotine acts through its receptors in VSMC to activate the ERK-Egr-1 signaling cascade that induces cell proliferation and exacerbates post-injury neointimal development.

Cited by 31 publications

References 37 publications

Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway

Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

Egr-1 Mediates Chronic Hypoxia-Induced Renal Interstitial Fibrosis via the PKC/ERK Pathway

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