Successful Transfection of Genes Using AAV-2/9 Vector in Swine Coronary and Peripheral Arteries

Pankajakshan, Divya; Makinde, Toluwalope O.; Gaurav, Rohit; Core, Michael Del; Hatzoudis, George; Pipinos, Iraklis I.; Agrawal, Devendra K.

doi:10.1016/j.jss.2011.02.032

Cited by 24 publications

(17 citation statements)

References 23 publications

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“…Total cellular RNA was extracted and mRNA expression was analyzed by Real Time PCR by methods described previously (27). Calculation of relative gene expression was done based on the differences in the threshold cycles (Ct).…”

Section: Methodsmentioning

confidence: 99%

Calcitriol Decreases Expression of Importin α3 and Attenuates RelA Translocation in Human Bronchial Smooth Muscle Cells

2012

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Purpose A potent immunomodulatory role of Vitamin D in both innate and adaptive immunity has recently been appreciated. In allergic asthma, activation of NF-κB induces transcription of various cytokines and chemokines involved in allergic airway inflammation. The nuclear import of activated NF-κB p50/RelA subunit is dependent on importin α3 (KPNA4) and importin α4 (KPNA3). In this study, we examined the role of importin α3 in immunomodulatory effect of calcitriol in human bronchial smooth muscle cells (HBSMCs). Methods Cultured HBSMCs were stimulated with calcitriol in the presence and absence of cytokines, TNF-α, IL-1β, and IL-10. The mRNA transcripts of importin α3 and α4 were analyzed using qPCR while protein expression of importin α3, α4 and nuclear RelA was analyzed by immunoblotting. Results Calcitriol significantly decreased mRNA and protein expression of importin α3 as well as nuclear protein expression of NF-κB p65 (RelA). The decreased activation of RelA by calcitriol was confirmed by decreased release of RelA-inducible molecules, including IL-5, IL-6 and IL-8, by HBSMCs upon calcitriol treatment. Calcitriol attenuated the effect of TNF-α and IL-1β to upregulate mRNA and protein expression of importin α3. IL-10 significantly decreased the TNF-α induced expression of importin α3 and this effect was further potentiated by calcitriol. Conclusions These data suggest that under inflammatory conditions, calcitriol decreases the expression of importin α3 resulting in decreased nuclear import of activated RelA. This could be a novel mechanism by which calcitriol could exert its immunomodulatory effects to reduce allergic airway inflammation and thus may alleviate the symptoms in allergic asthma.

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Section: Methodsmentioning

confidence: 99%

Calcitriol Decreases Expression of Importin α3 and Attenuates RelA Translocation in Human Bronchial Smooth Muscle Cells

2012

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“…Compared with native AAVs, vascular cell-specific peptide-modified AAVs have been shown to target gene delivery to vascular tissues, such as vascular endothelial cells (ECs), in vivo (81). Our group has successfully transfected a novel recombinant AAV-2/9 vector with SM22α promoter to the medial layer SMCs of swine coronary and peripheral arteries (82). It warrants mention that AAV-2/9 viral transduction in our study has no significant effect on serum amylase, fibrinogen and C-reactive protein levels, suggesting that AAV-2/9 is a safe and effective gene therapeutic vector for antirestenosis (82).…”

Section: Gene Delivery Systemsmentioning

confidence: 60%

“…Our group has successfully transfected a novel recombinant AAV-2/9 vector with SM22α promoter to the medial layer SMCs of swine coronary and peripheral arteries (82). It warrants mention that AAV-2/9 viral transduction in our study has no significant effect on serum amylase, fibrinogen and C-reactive protein levels, suggesting that AAV-2/9 is a safe and effective gene therapeutic vector for antirestenosis (82). Lentiviral vectors also provide a promising strategy for the treatment of cardiovascular diseases due to their durable gene transfer and their ability to govern efficiently.…”

Section: Gene Delivery Systemsmentioning

confidence: 99%

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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“…Persistent AAV-mediated transgene expression and inhibition of SMC proliferation and migration may help prevent late graft failure, provided the target cells are infected at the time of gene delivery. Recombinant AAVs are deleted of all viral genes and therefore have substantially lower immunogenicity than adenovirus, and they have shown an excellent safety profile in pre-clinical and clinical trials [66][67][68][69] . Despite these qualities, most currently used AAV vectors are suboptimal for targeting vein grafts, primarily due to their lack of native tropism for ECs and SMCs, the primary cellular elements of the intimal lesion 70,71 .…”

Section: Adeno-associated Virusmentioning

confidence: 99%

Gene Therapy for the Prevention of Vein Graft Disease

Mueller

Kontos

2015

Translating Gene Therapy to the Clinic

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Ischemic cardiovascular disease remains the leading cause of death worldwide. Despite advances in the medical management of atherosclerosis over the past several decades, many patients require arterial revascularization to reduce mortality and alleviate ischemic symptoms. Technological advancements have led to dramatic increases in the use of percutaneous and endovascular approaches, yet surgical revascularization (bypass surgery) with autologous vein grafts remains a mainstay of therapy for both coronary and peripheral artery disease. Although bypass surgery is highly efficacious in the short-term, long-term outcomes are limited by relatively high failure rates as a result of intimal hyperplasia, which is a common feature of vein graft disease.

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Successful Transfection of Genes Using AAV-2/9 Vector in Swine Coronary and Peripheral Arteries

Cited by 24 publications

References 23 publications

Calcitriol Decreases Expression of Importin α3 and Attenuates RelA Translocation in Human Bronchial Smooth Muscle Cells

Calcitriol Decreases Expression of Importin α3 and Attenuates RelA Translocation in Human Bronchial Smooth Muscle Cells

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

Gene Therapy for the Prevention of Vein Graft Disease

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