Oxidized thiols markedly amplify the vascular response to balloon injury in rabbits through a redox active metal-dependent pathway

Objective: Our aim was to assess whether exposure to oxidized thiols - a known usual consequence of oxidant stress - has the potential to affect the vascular repair response to angioplasty-induced injury. In addition, we also assessed the role of redox active metals in disulfide effects. Methods: In 82 rabbits submitted to overdistention of iliac arteries, the following variables were analyzed: neointimal thickening, immunoreactivity to Proliferating Cell Nuclear Antigen, and cellular and collagen densities. Results: A single intraarterial challenge of oxidized glutathione (GSSG, 6.5 mu mol/kg) during and immediately after injury triggered a marked increase of the vascular repair reaction, as follows: (A) at day 7 after injury, there was a 2.7-fold increase in proliferation (p < 0.001 vs. control); (B) at day 14, there was increase of intimal/medial area ratio to 1.35 +/- 0.14, vs. 0.56 +/- 0.08 in controls. Proliferating cells increased to 5.5 +/- 0.8 cells/mm(2), vs. 2.2 +/- 0.5 in controls (p < 0.002 for both variables). Overall cellularity was enhanced 2.2-fold; (C) at day 28, there was ongoing vessel wall proliferation, contrarily to controls. All GSSG effects were completely prevented by co-infusion of reduced glutathione (GSH) and were mimicked by cystine (6.5 mu mol/kg). The uninjured artery Showed no response to disulfides. To assess the role of redox active metals in GSSG action, the effects of 1,10-phenanthroline or N-CBZ-Pro-Leu-Gly hydroxamic acid (HXA), metal chelators with metalloproteinase inhibitor properties, were evaluated. Both compounds totally blocked the GSSG-induced amplification of vascular responses. In rabbits not exposed to GSSG, HXA decreased neointimal thickening by 50% (p < 0.05). Conclusions: Exposure to excess disulfide levels early after vascular balloon injury markedly amplified the late cellular response through interaction with redox active metals. These pathways can potentially mediate noxious effects of oxidative stress in vessels. (C) 1998 Elsevier Science B.V. All rights reserved.