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.
Highlights
Innate immunity is designed to initiate healing from vascular damage, an excess innate immune response is proven to accelerate atherosclerotic plaque growth [1,2]
While advances in medical therapy have been made in the prevention and treatment of native vascular atheroma development and acute thrombosis in unstable angina with lipid lowering agents and anti-platelet oranti-thrombotic agents, treatment for restenosis remains limited
The most effective treatment, proven to reduce restenosis after angioplasty or stent implant is the use of bare metal stents when compared to balloon angioplasty alone or the use of drug eluting stents when compared to balloon angioplastyor BMS [7,8,9,10,35,36,37]
Summary
Innate immunity is designed to initiate healing from vascular damage, an excess innate immune response is proven to accelerate atherosclerotic plaque growth [1,2]. More recent work has reportedendothelial dysfunction and inflammatory cell invasion at sites of coronary stent implant, causing increased risk of stent thrombosis [3,4,5,6,7]. DESrelease drugs that block cell proliferation, and potentially restenosis and inflammation, e.g. rapamycin and paclitaxel, but the foreign polymer and the metal in the stent canalso interfere withendothelial regrowth that protects against excess inflammation and thrombosis. This is proposed asa cause for late restenosis and thrombotic occlusions in DES and BMS. While the advent of BMS reduced the incidence of restenosis when compared to balloon angioplasty and coated DES stents further reduced restenosis, both types of stents are associated with persistent risk of restenosis and thrombosis, in the absence of adequate antiplatelet therapy [10]
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