A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

Abstract

SummaryRestenosis after percutaneous coronary intervention (PCI) is still a clinically serious problem. We examined the treatment efficacy of IMD-0354, a novel IKK inhibitor, on arteriopathy. Using C57BL/6J mice, a wire-injury model was prepared and the mice were intraperitoneally injected with IMD-0354 or vehicle twice a day. 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) on day 28. While enhanced expression of PCNA and NF-κB was observed in the untreated injured arteries, IMD-0354 significantly suppressed their expressions. Quantitative RT-PCR revealed that the expression of several inflammatory factors was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases. (Int Heart J 2012; 53: 133-138) Key words: IKK inhibitor, Chemical compound, Arterial remodeling, Inflammation, Smooth muscle R estenosis, which consists of neointimal formation after percutaneous coronary intervention (PCI), is a clinically serious problem. 1-3) Because inflammation is an essential pathological feature of neointimal formation, nuclear factor-kappa B (NF-κB) plays an important role in this process. 4) In humans, activated NF-κB is detected in restenotic lesions.5) Thus, NF-κB regulation has the potential to suppress its progression.Activation of NF-κB induces gene expression that leads to transactivation of adhesion molecules, cytokines and chemokines, promoting the inflammatory status involved in arterial injury. NF-κB is a dimer of the Rel family members and the most common active form is composed of p50 or p52 and p65. In resting cells, NF-κB is inactive and segregated in the cytoplasm, and bound to an inhibitory protein known as the inhibitor of NF-κB (IκB). NF-κB activation requires phosphorylation of IκB by IκB kinase (IKK) complex. The phosphorylated IκB is then ubiquitinated and degraded by proteasomes. Subsequently, the unbound NF-κB is translocated to the nucleus and binds to the promoter or enhancer of specific genes, including those involved in inflammatory reactions. 6)Recently, the first clinical use of an NF-κB decoy oligonucleotide at the site of coronary stenting for the prevention of restenosis was reported. 7,8) However, the indispensable role played by NF-κB in many biological processes has raised the concern that a complete shutdown of this pathway would have significant detrimental effects on normal cellular function. Instead, drugs that selectively target only inflammation-induced NF-κB activity would be of greater therapeutic value. IMD-0354, a novel NF-κB inhibitor, is a drug that specifically suppresses IKK-β activity.9) In this study, we investigated the effects of IMD-0354 on neointimal formation in vivo and VSMC proliferation in vitro. MethodsArterial injury models in mice: Male mice (C57BL/6, age 6-8 weeks, 20-25 g; Japa...

Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

“…The EAM ϩ vehicle group hearts demonstrated an increase of the heart-to-body weight ratio compared with that of the normal ϩ vehicle group. This ratio in the EAM ϩ IKKi (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) group was significantly smaller than that of the EAM ϩ vehicle group, whereas the EAM ϩ IKKi(14 -20) group was not statistically different compared with the EAM ϩ vehicle group. There was no significant difference of this ratio between the EAM ϩ IKKi (14 -20) group and the EAM ϩ IKKi(1-20) group (Fig.…”

“…Additionally, IVSTd value was reduced in the EAM ϩ IKKi (14 -20) group compared with that of the EAM ϩ vehicle group, although LVPWd value was not changed. There was no significant difference regarding IVSTd and LVPWd values between the EAM ϩ IKKi (14)(15)(16)(17)(18)(19)(20) group and the EAM ϩ IKKi(1-20) group (Table 1 and Fig. 1).…”

“…The severity of histological myocardial damage characterized by cell infiltration and fibrosis was significantly reduced in both the EAM ϩ IKKi (14 -20) group and the EAM ϩ IKKi(1-20) group compared with the EAM ϩ vehicle group. Additionally, it should be noted that there was no significant difference regarding this effect between the EAM ϩ IKKi(14 -20) group and the EAM ϩ IKKi (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) (14 -20)] was a trial to inspect utility as a therapeutic medicine of myocarditis. Meanwhile, there was no significant difference in echocardiographic parameters and histopathological findings between the normal ϩ vehicle group and the normal ϩ IKKi(1-20) group.…”

“…This drug is a selective IKK-␤ inhibitor, blocks IB␣ phosphorylation, and prevents NF-B p65 nuclear translocation. Some previous studies reported the beneficial effects of IMD-0354 and its prodrug on inflammation-related cardiovascular diseases (15,34,35,42). Therefore, regulation of NF-B activation by the IKK inhibitor might have a potent effect on the treatment of myocarditis.…”

IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment

“…It is known that they have nonequivalent functions and that activation of IKK-b, rather than IKK-a, participates in the primary pathway, by which proinflammatory stimuli activate NF-kB (18). Given that the indispensable roles played by NF-kB in many biologic processes raise the concern that a complete shutdown of this pathway would have significant detrimental effects on normal cellular function, drugs that selectively target only IKK-b activity could be of greater therapeutic value (19). IMD-0354 is a newly synthesized low molecular weight compound that selectively inhibits IKKb in the IKK complex.…”