Abstract 177: Pharmacological Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Intima Hyperplasia in Vein Grafts
Background. Veins structurally and functionally remodel after being grafted into the arterial circulation. Many factors regulate vein graft (VG) remodeling, but the overall process is not adequately understood. We reported previously that genetic deficiency of plasminogen activator inhibitor-1 (PAI-1) enhances intimal hyperplasia (IH) of murine VGs. However, the effects of pharmacological inhibition of PAI-1 on VG remodeling are unknown.
Methods and Results. We studied the effects of PAI-039, a small molecule that specifically inhibits free PAI-1, but not vitronectin (VN)-bound PAI-1, on VG remodeling. A segment of vena cava from a donor C57BL/6J mouse was inserted into the right carotid artery of a recipient mouse. Two groups were studied: 1) PAI-039 group, n=8; VG was coated with pluronic gel (50 μL) containing PAI-039 (25 μg/mL) during surgery; after surgery mice received PAI-039 (44 ug/kg by intraperitoneal [IP] injection) every other day for 3 weeks. 2) control group, n=8; mice received identical treatment, except that PAI-039 was omitted from pluronic gel and IP injection buffer. Four weeks later, mean intimal thickness and area were significantly less in PAI-039 treated mice than in controls (41.5±7.7 vs. 84.2±21.4 μm, and 0.17±0.044 vs. 0.34± 0.10 mm2, respectively, P<0.05). We also studied the effects of PAI-039 on proliferation of cultured venous smooth muscle cells (VSMC). PAI-039 (25 μM) significantly inhibited VSMC proliferation compared to vehicle control (0.65±0.073 vs. 0.82±0.078 AU [MTT assay], P<0.01).
Conclusion. PAI-039, a specific pharmacological PAI-1inhibitor, inhibits neointima formation in VGs. This finding contrasts with our previously reported data indicating that genetic PAI-1 deficiency promotes VG IH. This paradox is most likely explained by the pleiotropic actions of PAI-1 and the capacity of PAI-039 to inhibit free PAI-1, which is motogenic, but not VN-bound PAI-1, which inhibits SMC migration. Regardless of mechanism, our results suggest that pharmacological PAI-1 inhibition may be a useful strategy to inhibit adverse VG remodeling and emphasize that mouse knock-out models do not necessarily predict the biological impact of pharmacological inhibitors.
- © 2013 by American Heart Association, Inc.