Abstract 291: Multiple Mechanisms for the Inhibition of Intimal Hyperplasia by Herpes Simplex Virus Strain R7020
Intimal hyperplasia (IH) is the primary cause of vein bypass graft failure. Smooth muscle cells (SMCs) are a key element of IH as they phenotypically switch from a contractile to a synthetic state which may lead to IH. R7020 is an engineered strain of Herpes Simplex Virus-1 which inhibits IH in animal models. Although it has many characteristics which make it a strong candidate for use as a prophylaxis agent how it inhibits IH is not well understood. IH is multifaceted and R7020 infects a wide range of cell types regulating their cellular functions and pathways. Therefore we hypothesized that R7020 inhibits IH by altering multiple cellular functions and cell types. The objective of this study was to identify mechanisms used by R7020 to function in blood vessels that may contribute to its inhibition of IH. In this study the cytopathic effect of R7020 on SMCs was determined in vitro and in a rabbit IH model. The effects of R7020 on SMC viability and the adhesion of peripheral blood mononuclear cells (PBMCs) to SMCs were quantified in the absence and presence of TNF-α. Microarray analysis was used to identify genes whose expression was altered by R7020 in vivo. The cytopathic effects which include filopodia positive for R7020 tegument proteins extending from cell to cell and the formation of syncytia suggest that R7020 remains cell associated after egress and spreads cell to cell instead of by diffusion through the extracellular fluid. The directionality of the filopodia in vivo suggests that the virus preferentially travels from the media towards the intima targeting the SMCs that would lead to IH. The formation of syncytia would also inhibit SMC proliferation as cells that form syncytia do not proliferate. In addition, R7020 induced the fusion of PBMCs with syncytia which may limit the effect of macrophages on IH. Furthermore, R7020 inhibited the proliferative effect of TNF-α, an inflammatory cytokine associated with increased IH. Microarray analysis detected a significant change in the expression of 58 genes in R7020 infected arteries relative to non-infected at 24 h. The encoded proteins are associated with the immune system, cell death, proliferation/motility and vascular tone. Thus this study identifies multiple mechanisms which R7020 may be using to inhibit IH.
Author Disclosures: S. McCormick: None. C.L. Skelly: Other; Modest; Founder Maji Therapuertics.
- © 2015 by American Heart Association, Inc.