SOCS3 promotor hypermethylation and STAT3-NF-κB interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells

Dhar, Kajari; Rakesh, Kriti; Pankajakshan, Divya; Agrawal, Devendra K.

doi:10.1152/ajpheart.00570.2012

Cited by 46 publications

(47 citation statements)

References 52 publications

(45 reference statements)

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“…In HCASMCs, we reported that only IGF-1 treatment, but not TNF-α, induces activation of STAT3, whereas NF-κB was activated only in response to TNF-α treatment, but not IGF-1, and the co-immunoprecipitation results showed the binding of activated STAT3 to NF-κB in the cells that were treated with both TNF-α and IGF-1 [10]. These results not only suggest that SOCS3 expression was pre-transcriptionally inhibited, but it also essentiates the role of canonical JAK/STAT/NF-κB pathway in regulating SOCS3 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study showed that SOCS3 expression was dramatically decreased in porcine coronary artery smooth muscle cells (PCASMCs) in presence of TNF-α and IGF-1 [9]. We also showed that the SOCS3 promoter region was methylated when human coronary artery smooth muscle cells (HCASMCs) were treated with both TNF-α and IGF-1, which resulted in the inhibition of SOCS3 expression [10]. …”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3

2015

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Previously we found decreased expression of SOCS3 in neointimal hyperplastic region following balloon angioplasty in atherosclerotic micro swine. In our recent in vitro studies using human coronary artery smooth muscle cells (HCASMC), we observed the inhibition of SOCS3 expression in the presence of both TNF-α and IGF-1, correlating with the in-vivo findings in microswine. We also reported that two independent mechanisms, JAK/STAT3/NFκB and promoter methylation of SOCS3 were responsible for TNF-α– and IGF-1-induced SOCS3 inhibition. In this study, using miRNA array and gene expression approaches, we explored the molecular mechanisms involved in the above SOCS3 repression and identified several miRNAs that are associated with the regulation of SOCS3 expression. Our miRNA expression profiling revealed profound down-regulation of two specific miRNAs, hsa-miR-758 and hsa-miR-1264, whose expression levels decreased by 8–10 folds when HCASMCs were treated with both TNF-α and IGF-1. This was accompanied with a significant up-regulation of three specific miRNAs, hsa-miR-155, hsa-miR-146b-5p and hsa-miR-146a, which showed about 3–7 fold increases in their expression levels. Importantly, we also found that the miRNA hsa-miR-1264 targets DNA methyltransferase-1 (DNMT1) transcripts by binding to its 3’UTR region to affect its expression. Expression of hsa-miR-1264 in HCASMCs not only resulted in decreased DNMT1 mRNA transcripts but it also increased SOCS3 expression. The treatment with TNF-α and IGF-1 resulted in drastic decrease in hsa-miR-1264 levels with no change in the expression of DNMT1. Consequently, the DNMT1 activity caused hypermethylation in the CpG island of the SOCS3 promoter region and inhibited its expression. This could be a causative epigenetic mechanism associated with TNF-α– and IGF-1-induced smooth muscle cell proliferation involved in the pathogenesis of coronary artery hyperplasia and restenosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3

2015

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“…Recently, our laboratory has found a significant reduction in SOCS3 expression in the neointimal lesion after balloon angioplasty in coronary arteries of atherosclerotic swine (52). In addition, our laboratory demonstrated that hypermethylation of the SOCS3 gene in SMCs could be an underlying mechanism of intimal hyperplasia and restenosis, suggesting that inhibition of SOCS3 promoter methylation is a potential anti-neointimal hyperplasia target (53).…”

Section: Antineointimal Hyperplasiamentioning

confidence: 80%

Gene therapy for in-stent restenosis: Targets and delivery system

Yin¹,

Agrawal²

2014

Curr Res Cardiol

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Despite the increased use of drug-eluting stents (DES), the incidence of in-stent restenosis (ISR) requiring target vessel revascularization remains unacceptably high (1,2). The incidence rate of ISR requiring target vessel revascularization (ie, 'DES failure') in the United States alone was conservatively estimated to be 10%, and may be more common in patients with diabetes mellitus (3). Although the pathophysiology of DES failure is complex, histopathological changes of in-stent neointima following directional atherectomy at the time of reintervention have been shown to be remarkably similar between bare-metal stents (BMS) and DES, suggesting that a process mediated by the endothelial injury, inflammation, proliferation and migration of vascular smooth muscle cells (VSMCs), and thrombosis plays the same important role in the progress of ISR of DES (4,5). In addition, antiproliferative drugs in DES, primarily aimed at preventing VSMC proliferation (which is central to the pathogenesis of ISR), also perturb endothelial recovery (6), which consequently increases the risk for subacute in-stent thrombosis and results in late stent thrombosis (ST) (7). Furthermore, polymer coatings on DES induce a distinct inflammatory reaction compared with bare metal surfaces (8). These results raise serious questions regarding the long-term durability and efficacy of DES, thereby resulting in an urgent need to develop new therapies to prevent restenosis. The present review focuses on the progress made to date in the use of gene therapy, including catheter-based gene delivery and gene-eluting stents (GES), to prevent ISR. We will also discuss the current and promising application of magnetic targeting gene delivery systems for antirestenosis therapy. Evolution of antirEstEnosis thErapyIn the past several decades, percutaneous transluminal coronary angioplasties have revolutionized the treatment of atherosclerosis-related cardiovascular disease. At the same time, tremendous efforts have also been made to reduce the incidence of restenosis after percutaneous transluminal coronary angioplasties (9). During the time in which 'plain old balloon angioplasty' was prevalent, rates of acute and chronic vessel occlusion were higher (30% to 56%), secondary to acute/chronic recoil and constrictive remodelling (10). These problems led to the development of a second revolutionary treatment, BMS, which were first implanted in 1986 (11). Although this 'bailout' scaffold significantly reduced the issue of acute and chronic recoil, its application was ultimately hampered by the risk for subacute thrombotic coronary artery occlusion and neointimal hyperplasia (12). The restenosis rates with BMS were reported to be between 16% and 44%, with higher rates of stenosis attributable to several risk factors, particularly long lesion length and small vessel calibre (1,13). Considerable progress to reduce the incidence of restenosis was made by the advent of DES, which are composed of a metallic stent, a polymer-based drug delivery platform and a pharmacolog...

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“…Smooth muscle cells Intimal hyperplasia and restenosis [15] Mitofusin-2 [16] Extracellular superoxide dismutase Cell-specific expression; protection from oxidative stress and modulation of vascular tone [17] Sixth CTCF-binding site upstream of H19; insulin like growth factor-2…”

Section: Histone Methylationmentioning

confidence: 99%

The relevance of epigenetics to occlusive cerebral and peripheral arterial disease

2015

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Athero-thrombosis of the arteries supplying the brain and lower limb are the main causes of stroke and limb loss. New therapies are needed to improve the outcomes of athero-thrombosis. Recent evidence suggests a role for epigenetic changes in the development and progression of ischaemic injury due to atherosclerotic occlusion of peripheral arteries. DNA hypermethylation have been associated with cardiovascular diseases. Histone post-translational modifications have also been implicated in atherosclerosis. Oxidized low-density lipoprotein regulated pro-inflammatory gene expression within endothelial cells is controlled by phosphorylation/acetylation of histone H3 and acetylation of histone H4 for example. There are a number of challenges in translating the growing evidence implicating epigenetics in atherosclerosis to improved therapies for patients. These include the small therapeutic window in conditions such as acute stroke and critical limb ischaemia, since interventions introduced in such patients need to act rapidly and be safe in elderly patients with many co-morbidities. Pre-clinical animal experiments have also reported conflicting effects of some novel epigenetic drugs, which suggest that further in-depth studies are required to better understand their efficacy in resolving ischaemic injury. Effective ways of dealing with these challenges are needed before epigenetic approaches to therapy can be introduced into practice.

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SOCS3 promotor hypermethylation and STAT3-NF-κB interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells

Cited by 46 publications

References 52 publications

Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3

Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3

Gene therapy for in-stent restenosis: Targets and delivery system

The relevance of epigenetics to occlusive cerebral and peripheral arterial disease

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