Attenuated herpes simplex virus 1 blocks arterial apoptosis and intimal hyperplasia induced by balloon angioplasty and reduced blood flow

Abstract

Injury caused by distention of the arterial wall by balloon angioplasty can result in apoptosis and vascular smooth muscle cell proliferation. Here, we report that a brief exposure of the arterial lumen to a genetically engineered, attenuated herpes simplex virus 1 blocks activation of caspase 3-dependent apoptosis and MAPKdependent cell proliferation induced by carotid artery balloon angioplasty and ligation to reduce blood flow. The procedure enables the restoration of the endothelial cell layer lining the lumen and prevents neointimal hyperplasia and restenosis. These findings have a broad application in prevention of balloon angioplasty-induced restenosis.neointimal hyperplasia ͉ restenosis ͉ vascular smooth muscle cells ͉ endothelial cells

Concomitant Proliferation and Caspase-3 Mediated Apoptosis in Response to Low Shear Stress and Balloon Injury

“…Representative samples from all of the different cohorts; sham (n=6)(28 day carotid artery morphology data from 4 of the 6 sham animals was previously published 33), low τ (n=4), balloon injury (n=4), and combined low τ and balloon injury (n=4), are shown in Figure 5, and numeric data given in Table 3. All arteries remained patent at sacrifice at 28 days.…”

Delayed inhaled carbon monoxide mediates the regression of established neointimal lesions

“…Reddy et al (25) showed that treatment of balloon injured arteries with rapamycin-loaded nanoparticles inhibited arterial wall apoptosis and improved re-endothelialization and reduced IH. Finally, Skelly et al (26) expressed an attenuated herpes simplex virus which inhibited apoptosis in injured arteries and attenuated IH. While these studies identified that apoptosis following arterial injury can favorably limit IH, they also suggest that ongoing apoptosis may contribute to a persistent injury phenotype.…”

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

“…17, 18 Of the mutants tested, the more promising are based on deletions of the γ 1 34.5 genes. The gene product, infected cell protein (ICP) 34.5 is a multifunctional protein engaged primarily in blocking host defense mechanisms.…”

“…R3616 has a very high margin of safety: intra-cerebral injection of G207 (similar to R3616 but with an additional insertion mutation of ICP 6) at doses as high as 3 × 10 9 plaque forming units (pfu) into patients with the malignant brain tumor glioblastoma multiforme caused no serious adverse effects. 24 In prior reports we showed that R3616 and R7020 are efficacious in the treatment of intimal hyperplasia, 17, 18 but the question arose whether engineered HSV-1 virus' anti-proliferative activity, as it applies to the cardiovascular system, was dependent on activated MEK. As a control we used the R7020 mutant.…”