Modulating vascular intimal hyperplasia using HSV-1 mutant requires activated MEK

Skelly, Chris; He, Qi; Spiguel, Lisa; McCormick, Susan; Weichselbaum, Ralph R.

doi:10.1038/gt.2012.26

Cited by 2 publications

(3 citation statements)

References 35 publications

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“…We have previously shown that R7020 inhibits IH in a balloon injury low flow model [ 19 ]. The results from this study indicate some of the mechanisms R7020 may use to accomplish this including ones that are a consequence of R7020 spreading.…”

Section: Discussionmentioning

confidence: 99%

“…At this point the virus can be delivered locally by injecting it into the lumen eliminating the need for systemic administration. Unlike vectors, which require pathologically high pressures to effectively penetrate the vessel wall, R7020 is delivered efficiently under physiological pressures [ 17 – 19 ]. Once in the wall, R7020 preferentially infects vascular SMCs and inhibits cellular proliferation, and will do so in immune-competent hosts [ 17 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, how R7020 inhibits IH is not well established. We have shown that its anti-proliferative effect is via a caspase 3 and mitogen-activated protein kinase kinase (MEK) dependent mechanism [ 18 , 19 ]. However, IH is multifaceted and R7020 infects and regulates the cellular pathways and functions of a wide range of cell types.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for the Use of Multiple Mechanisms by Herpes Simplex Virus-1 R7020 to Inhibit Intimal Hyperplasia

McCormick

Stern

et al. 2015

PLoS ONE

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Intimal hyperplasia (IH) is the primary cause of vein bypass graft failure. The smooth muscle cell (SMC) is a key element of IH as it phenotypically switches from a contractile to a synthetic state which can become pathological. R7020, which is an engineered strain of Herpes Simplex Virus-1, inhibits IH in animal models. Although it has many characteristics which make it a strong candidate for use as a prophylactic agent how it inhibits IH is not well understood. The objective of this study was to identify modes of action used by R7020 to function in blood vessels that may also contribute to its inhibition of IH. The cytopathic effect of R7020 on SMCs was determined in vitro and in a rabbit IH model. In vitro assays with R7020 infected SMCs were used to quantify the effect of dose on the release kinetics of the virus as well as the effects of R7020 on cell viability and the adhesion of peripheral blood mononuclear cells (PBMCs) to SMCs in the absence and presence of tumor necrosis factor alpha (TNF-α). The observed cytopathic effect, which included R7020 positive filopodia that extend from cell to cell and the formation of syncytia, suggests that R7020 remains cell associated after egress and spreads cell to cell instead of by diffusion through the extracellular fluid. This would allow the virus to rapidly infect vascular cells while evading the immune system. The directionality of the filopodia in vivo suggests that the virus preferentially travels from the media towards the intima targeting SMCs that would lead to IH. The formation of syncytia would inhibit SMC proliferation as incorporated cells are not able to multiply. It was also observed that R7020 induced the fusion of PBMCs with syncytia suggesting the virus may limit the effect of macrophages on IH. Furthermore, R7020 inhibited the proliferative effect of TNF-α, an inflammatory cytokine associated with increased IH. Thus, the results of this study suggest that R7020 inhibits IH through multiple mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for the Use of Multiple Mechanisms by Herpes Simplex Virus-1 R7020 to Inhibit Intimal Hyperplasia

McCormick

Stern

et al. 2015

PLoS ONE

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Oncogenes: The Passport for Viral Oncolysis through PKR Inhibition

Fernandes

2016

Biomark�Cancer

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The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death.

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Modulating vascular intimal hyperplasia using HSV-1 mutant requires activated MEK

Cited by 2 publications

References 35 publications

Evidence for the Use of Multiple Mechanisms by Herpes Simplex Virus-1 R7020 to Inhibit Intimal Hyperplasia

Evidence for the Use of Multiple Mechanisms by Herpes Simplex Virus-1 R7020 to Inhibit Intimal Hyperplasia

Oncogenes: The Passport for Viral Oncolysis through PKR Inhibition

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