Abstract
Activated protein C (APC), an endogenous protein, inhibits inflammation and thrombosis and interrupts the coagulation cascade. Here, we investigated the effect of human recombinant APC on the development of neointimal hyperplasia in porcine coronary arteries. Yukon Choice bare metal stents were coated with 2.6 µg APC/mm(2). Under general anesthesia, APC-coated and bare stents were implanted in the left anterior descending and circumflex coronary arteries of 10 domestic pigs. During the 4-week follow-up, animals were treated with dual antiplatelet therapy and neointimal hyperplasia was evaluated via histology. Scanning electron microscopy indicated successful but unequal coating of stents with APC; nearly complete drug release occurred within 4 h. Enzyme-linked immunosorbent assay revealed that intracoronary stent implantation rapidly increased the levels of monocyte chemoattractant protein-1, an effect that was inhibited by APC release from the coated stent. Fibrin deposition and adventitial inflammation were significantly decreased 1 month after implanting APC-coated stents versus bare stents, paralleled by significantly smaller neointimal area (0.98 ± 0.92 vs. 1.44 ± 0.91 mm(2), P = 0.028), higher lumen area (3.47 ± 0.94 vs. 3.06 ± 0.91 mm(2), P = 0.046), and lower stenosis area (22.2 ± 21.2% vs. 32.1 ± 20.1%, P = 0.034). Endothelialization was complete with APC-coated but not bare (90%) stents. P-selectin immunostaining revealed significantly fewer activated endothelial cells in the neointima in the APC group (4.6 ± 1.9 vs. 11.6 ± 4.1%, P < 0.001). Thus, short exposure of coronary arteries to APC reduced inflammatory responses, neointimal proliferation, and in-stent restenosis, offering a promising therapy to improve clinical outcomes of coronary stenting. However, coating stents with APC for prolonged, controlled drug release remains technically challenging.