Suppressor of cytokine signaling-3 and intimal hyperplasia in porcine coronary arteries following coronary intervention

Gupta, Gaurav; Dhar, Kajari; Core, Michael G. Del; Hunter, William J.; Hatzoudis, Georgios I.; Agrawal, Devendra K.

doi:10.1016/j.yexmp.2011.04.004

Cited by 25 publications

(34 citation statements)

References 33 publications

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“…However, the most intriguing and novel finding is that the stimulation of hCASMCs simultaneously with TNF-␣ and IGF-1 significantly decreases the SOCS3 mRNA and protein expression. This supports our recent report in a porcine model (11). However, the underlying molecular mechanisms are unclear.…”

Section: Discussionsupporting

confidence: 91%

“…Recently, we reported a significant reduction in the SOCS3 expression in the neointimal lesion after balloon angioplasty in coronary arteries of atherosclerotic swine (11). These neointimal lesions are also highly positive to both TNF-␣ and IGF-1.…”

mentioning

confidence: 82%

“…These neointimal lesions are also highly positive to both TNF-␣ and IGF-1. In the in vitro studies, treatment of porcine coronary artery smooth muscle cells with both TNF-␣ and IGF-1 decreased SOCS3 expression (11). It was indeed interesting to find an upregulation of SOCS3 expression in porcine coronary artery smooth muscle cells when treated individually with either IGF-1 or TNF-␣.…”

mentioning

confidence: 93%

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

Dhar

Rakesh

Pankajakshan

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Agrawal DK. SOCS3 promotor hypermethylation and STAT3-NF-B interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells. Am J Physiol Heart Circ Physiol 304: H776 -H785, 2013. First published January 18, 2013 doi:10.1152/ajpheart.00570.2012.-Suppressor of cytokine signaling-3 (SOCS3) is an intracellular negative regulator of cytokine signaling pathway. We recently found significant reduction in SOCS3 expression in coronary artery smooth muscle cells (CASMCs) of atherosclerotic swine and also in vitro cultured cells. Here, we investigated the underlying mechanisms of SOCS3 downregulation by IGF-1 and TNF-␣ in human CASMCs(hCASMCs). We propose that hypermethylation of CpG islands in the SOCS3 promoter is responsible for decrease in SOCS3 expression involving STAT3 and NFkB-p65 interaction. Western blot and qPCR data revealed significant upregulation of SOCS3 (6-to 10-fold) in hCASMC when treated individually with TNF-␣ (100 ng/ml) or IGF-1 (100 ng/ml). However, a significant decrease (5-fold) was observed by the combined treatment with TNF-␣ and IGF-1 compared with individual stimulation. IGF-1 phosphorylated STAT3 and TNF-␣-activated NF-B in hCASMCs. In the nuclear extract of hCASMCs stimulated with both TNF-␣ and IGF-1, there was an interaction between NF-B-p65 and pSTAT3, as determined by co-immunoprecipitation. Knockdown of STAT3 by small interfering RNA abolished SOCS3 expression in response to IGF-1. Methylation-specific PCR confirmed hypermethylation of SOCS3 promoter in hCASMCs stimulated with both TNF-␣ and IGF-1, and this was positively associated with elevated levels of DNA methyltransferase-I (9-to 10-fold). Knockdown of DNMT1 increased SOCS3 expression in IGF-1ϩTNF-␣-stimulated cells. Downregulation of SOCS3 in the presence of both TNF-␣ and IGF-1 in hCASMCs is due to SOCS3 promoter hypermethylation involving STAT3-NFkBp65 interaction. Because TNF-␣ and IGF-1 are released due to mechanical injury during coronary intervention, hypermethylation of SOCS3 gene could be an underlying mechanism of intimal hyperplasia and restenosis. cell signaling; cytokines; growth factors; hypermethylation; intimal hyperplasia; smooth muscle cells; suppressor of cytokine signaling 3; signal transducer and activator of transcription

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Section: Discussionsupporting

confidence: 91%

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confidence: 82%

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confidence: 93%

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

Dhar

Rakesh

Pankajakshan

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…The porcine coronary and rabbit iliac artery models were used, with agents administered systemically or locally. 21 Coronary stents were developed to overcome acute closure and acute recoil. Charles Dotter introduced the concept of stenting by placing the first ''coil spring graft'' in the femoral artery of a dog.…”

Section: History Of Animals In Stent Developmentmentioning

confidence: 99%

Role of Animal Models in Coronary Stenting

et al. 2015

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Coronary angioplasty initially employed balloon dilatation only. This technique revolutionized the treatment of coronary artery disease, although outcomes were compromised by acute vessel closure, late constrictive remodeling, and restenosis due to neointimal proliferation. These processes were studied in animal models, which contributed to understanding the biology of endovascular arterial injury. Coronary stents overcome acute recoil, with improvements in the design and metallurgy since then, leading to the development of drug-eluting stents and bioresorbable scaffolds. These devices now undergo computer modeling and benchtop and animal testing before evaluation in clinical trials. Animal models, including rabbit, sheep, dog and pig are available, all with individual benefits and limitations. In smaller mammals, such as mouse and rabbit, the target for stenting is generally the aorta; whereas in larger animals, such as the pig, it is generally the coronary artery. The pig coronary stenting model is a gold-standard for evaluating safety; but insights into biomechanical properties, the biology of stenting, and efficacy in controlling neointimal proliferation can also be gained. Intra-coronary imaging modalities such as intravascular ultrasound and optical coherence tomography allow precise serial evaluation in vivo, and recent developments in genetically modified animal models of atherosclerosis provide realistic test beds for future stents and scaffolds.

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“…Suppressor of cytokine signalling-3 (SOCS3) protein decreases the JAK/STAT signalling by blocking the JAK tyrosine kinase activity and the activation of STAT factors, suggesting that it is a novel antineointimal hyperplasia target. 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: 77%

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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Suppressor of cytokine signaling-3 and intimal hyperplasia in porcine coronary arteries following coronary intervention

Cited by 25 publications

References 33 publications

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

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

Role of Animal Models in Coronary Stenting

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

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