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 af fect the vascular repair response to angioplasty-induced injury. In ad dition, we also assessed the role of redox active metals in disulfide effects. Methods: In 82 rabbits submitted to overdistention of iliac a rteries, the following variables were analyzed: neointimal thickening, immunoreactivity to Proliferating Cell Nuclear Antigen, and cellular and collagen densities. Results: A single intraarterial challenge of o xidized glutathione (GSSG, 6.5 mu mol/kg) during and immediately after injury triggered a marked increase of the vascular repair reaction, a s 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 incre ase of intimal/medial area ratio to 1.35 +/- 0.14, vs. 0.56 +/- 0.08 i n 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 ce llularity was enhanced 2.2-fold; (C) at day 28, there was ongoing vess el wall proliferation, contrarily to controls. All GSSG effects were c ompletely prevented by co-infusion of reduced glutathione (GSH) and we re 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 h ydroxamic acid (HXA), metal chelators with metalloproteinase inhibitor properties, were evaluated. Both compounds totally blocked the GSSG-i nduced amplification of vascular responses. In rabbits not exposed to GSSG, HXA decreased neointimal thickening by 50% (p < 0.05). Conclusio ns: Exposure to excess disulfide levels early after vascular balloon i njury markedly amplified the late cellular response through interactio n with redox active metals. These pathways can potentially mediate nox ious effects of oxidative stress in vessels. (C) 1998 Elsevier Science B.V. All rights reserved.