Oxidative stress as a signaling mechanism of the vascular response to injury: The redox hypothesis of restenosis

The prominent role of redox processes in tissue injury and in vascular cell signaling suggest their involvement in the repair reaction to vessel injur y, which is a key determinant of restenosis post-angioplasty. Experimental studies showed a protective effect of superoxide dismutase or antioxidants on vasospasm, neointimal thickening or remodeling after balloon injury. It was also shown that oxidized thiols induce chelatable metal-dependent ampli fication of the vascular repair reaction. Ongoing or completed clinical tri als show a promising effect of the antioxidant probucol against restenosis. However, few studies addressed the molecular physiological mechanisms unde rlying the redox hypothesis of restenosis. We recently showed evidence for marked oxidative stress early after balloon injury, with superoxide product ion mediated primarily by non-endothelial NAD(P)H oxidase-type flavoenzyme( s). This effect was closely related to the degree of injury. There is evide nce supporting a role for such early redox processes in apoptotic cell loss and NF-kappa B activation. We present new data on the time course of oxida tive stress after balloon injury of intact rabbit iliac arteries. Our data show that despite substantial neointimal growth and lumen narrowing, supero xide production and glutathione levels are unaltered at day 14 and 28 after balloon injury. At day 7 after injury, the peak neointimal proliferation i n this model, there was significant decrease of vascular superoxide dismuta se activity, without clear evidence of spontaneous superoxide production. T hus, oxidative stress after injury is likely to be an early transient event , which parallels the inflammatory and proliferative phases of the vascular response. We propose that such early redox processes act as dose-dependent signal transducers of gene programs that affect the final repair. (C) 2000 Elsevier Science B.V. All rights reserved.