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Herpes Simplex Virus Mutant Blocks Shear And Mechanically Induced Apoptosis: A Possible Mechanism For The Prevention Of Restenosis

Amito Chandiwal, James Vosciky, Bernard Roizman, Ralph Weichselbaum, Lewis Schwartz, Christopher Skelly ∙ University of Chicago, Chicago, IL

Objectives: Vascular remodeling is a natural response of blood vessels to injury and/or changes in shear stress and manifests as neointimal thickening (NIT). Previous strategies to prevent NIT have focused on inducing apoptosis. The vector system of a γ134.5-deficient herpes simplex virus (HSV) is a novel system that has been characterized and found to be efficacious in the prevention of NIT. Previous studies have shown that the HSV-1 blocks execution of the cell death program triggered by expression of viral genes, but the exact mechanism for the prevention of NIT is unclear; the purpose of this abstract is to begin to elucidate the mechanisms that an HSV mutant employs to suppress NIT by specifically studying apoptosis during the early stages of infection.
Methods: The common carotid artery (CCA) of 21 NZ White Rabbits underwent balloon injury (3 passes of a 3F balloon catheter), and then exposed intraluminally either to vehicle (PBS, n=7) or HSV-1 R7020 (1x109 pfu/ml, n=7). The CCA was then restricted by ligating over a 0.014 guide wire distal to the cranial thyroid branch. Sham controls were included. At 3 days (n=9), the CCA was assessed for apoptosis by TUNEL immunostaining. At 4 weeks, the remaining arteries (n=12) were perfusion-fixed and histomorphometry performed after staining with WVG. One Way ANOVA was used for statistical analysis and significance assigned at p<0.05.
Results: All arteries were patent at sacrifice. Assessment of apoptosis at day 3 by TUNEL immunostaining revealed significantly greater apoptosis in the control group as compared to sham and the R7020 treated groups (Fig.1). There was a significant decrease in NIT, medial and total wall thickness in the R7020 treated group as compared to the control. (Table 1 & Fig.2).
Conclusions: A brief exposure of the artery to R7020 resulted in a significant decrease in NIT compared to control. Apoptosis induced by low shear stress and balloon injury was not seen in the HSV-1 treated group. This may suggest a possible mechanism for prevention of restenosis. Previous studies have shown that the HSV-1 blocks apoptosis triggered by expression of viral genes. The ability of HSV-1 to block apoptosis may then allow for viral propagation and ultimate cytolysis of the proliferating VSMCs, thereby leading to decreased NIT.