Abstract 10489: A Novel IKK Inhibitor Prevents Progression of Neointimal Formation After Arterial Injury in Mice
Introduction: Restenosis, which is composed of neointimal formation after the percutaneous coronary intervention (PCI), is still a clinically serious problem. In this study, we verified the treatment efficacy of IMD-0354, a novel IKK inhibitor on the arteriopathy.
Hypothesis: We assessed the hypothesis that IMD-0354 inhibited neointimal formation after arterial injury by preventing inflammation and vascular smooth muscle cell (VSMC) proliferation.
Methods: Using C57BL/6J mice, we made a wire-injury model and intraperitoneally injected IMD-0354 or vehicle twice a day. The arteries were harvested for pathological and molecular analysis on day 28 after injury. We measured the inflammatory responses in cultured VSMC and macrophages derived from the mice.
Results: The vehicle-treated injured arteries showed significantly thickened intima (3.77±0.59, n=8), however, IMD-0354 suppressed its progression (1.62±0.22, n=10, p<0.05). While enhanced expression of PCNA and NF-kB was observed in the non-treated injured arteries, IMD-0354 significantly suppressed their expression. Immunohistochemistry revealed that macrophages were primarily responsible for NF-kB activation compared to VSMC. Quantitative RT-PCR revealed that the expression of several inflammatory factors (IL-6, MCP-1, COX-2, ICAM-1, and MMP-3) was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. To further investigate the mechanisms, we performed in vitro studies. TNF-alpha stimulated macrophage induced VSMC proliferation (0.61±0.02, n=6), while IMD-0354 attenuated this proliferation (0.21±0.01, n=6, p<0.05).
Conclusion: Inhibition of NF-kB activation using IMD-0354 can reduce proinflammatory reactions and VSMC proliferation in vascular remodeling. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases.
- © 2011 by American Heart Association, Inc.