© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Oxidative stress as a signaling mechanism of the vascular response to injury
The redox hypothesis of restenosis
aHeart Institute (InCor), University of São Paulo Medical School, Av. Eneas Carvalho Aguiar, 44, subsolo, CEP 05403-000, São Paulo, Brazil
bEmergency Medicine Department, University of São Paulo Medical School, São Paulo, Brazil
cFederal University of Santa Catarina, Florianópolis, Brazil
* Corresponding author. Tel.: +55-11-853-7887; fax: +55-11-282-2354 expfrancisco{at}incor.usp.br
The prominent role of redox processes in tissue injury and in vascular cell signaling suggest their involvement in the repair reaction to vessel injury, 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 amplification of the vascular repair reaction. Ongoing or completed clinical trials show a promising effect of the antioxidant probucol against restenosis. However, few studies addressed the molecular physiological mechanisms underlying the redox hypothesis of restenosis. We recently showed evidence for marked oxidative stress early after balloon injury, with superoxide production mediated primarily by non-endothelial NAD(P)H oxidase-type flavoenzyme(s). This effect was closely related to the degree of injury. There is evidence 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 oxidative stress after balloon injury of intact rabbit iliac arteries. Our data show that despite substantial neointimal growth and lumen narrowing, superoxide production and glutathione levels are unaltered at day 14 and 28 after balloon injury. At day 7 after injury, the peak neointimal proliferation in this model, there was significant decrease of vascular superoxide dismutase activity, without clear evidence of spontaneous superoxide production. Thus, 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.
KEYWORDS Angioplasty; Restenosis; Free radicals; Endothelial factors; Atherosclerosis
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