Comparative Analysis of Plaque Growth after Arterial Stent Implant with Anti-Inflammatory Chemokine and Serine Protease Inhibitors Treatment

Abstract

Rationale -Inflammation is up-regulated at sites ofstent implant, whether bare metal or drug-eluting stents (DES), increasingneointimal plaque growth (termed restenosis). Although stent implant,, particularly DES, reduces recurrent plaque growth, restenosis still occurs. Inflammatory macrophages and T lymphocytes invadesites withendothelial injury and implanted foreign metal and polymersincreaseendothelial dysfunction, plaque growthand thrombosis. Chemokines attract inflammatory cells and coagulation pathway serine proteases regulate clot formation, metalloproteases, and inflammation. Large DNA viruses secrete highly active immune modulators that block host defenses, some of which are potent inhibitors of pathways that drive restenosis. We examine here two virus-derived anti-inflammatory proteins as potential anti-restenosis agents in a rabbit angioplasty and stent implant model;1) M-T7,a chemokine modulator and 2) Serp-1, a serine protease inhibitor (serpin). Results -Inhibition of inflammatory cell activation by eitherM-T7 or Serp-1protein infusions significantly reduced in-stent plaque growth. M-T7 displayed a trend toward more effective inhibition when given at lower doses and for shorter dosage times. Conclusions -1) Inhibition of either chemokine or serine protease pathways effectively reduces inflammation and intimal hyperplasia after balloon angioplasty and stent implant (restenosis) in cholesterol fed rabbits. 2) Chemokine and serine protease pathways provide excellent therapeutic targets for inhibition of restenosis.