The attenuated response to angiotensin II in INV-403 rabbits was paralleled by decreased mRNA expression of angiotensin II receptor, type 1 (AT1) receptor (Figure 3C). weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factorB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IB) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IB phosphorylation via inhibition of IB kinase 2 (IKK2). == Conclusion == INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factorB signaling. Keywords: atherosclerosis, macrophages, vascular biology Atherosclerosis is a complex, multifactorial disease that involves distinct stages that accrue over a lifetime. 1, 2Oxidative stress and inflammation play a fundamental role in the genesis of all of these processes36and represent targets for intervention. Current approved therapies for the prevention and treatment of atherosclerosis suffer from important drawbacks, including the inability to address multiple mechanisms involved in progression in atherosclerosis and side effects, especially those related to unrecognized off-target effects, when targeting highly specific pathways. 7, 8 Dietary approaches are inherently powerful as they are safe and can be initiated early and over the long term for an individual, providing for the greatest likelihood for success. 917A number of dietary strategies have the capability of simultaneously addressing distinct pathophysiologically relevant processes. 1825Successful implementation, however , warrants complete understanding of the effects of the intervention on these pathways. 19In addition, no single dietary intervention combines all aspects of an ideal intervention. 17, 18, 2632Thus, fortification of existing dietary regimens with simple and safe components derived from other regimens may be preferable. 17, 33In many Asian cultures, ingredients used in cooking have been implicated in health benefits over thousands of years. 34Oil RH-II/GuB seeds, such as flaxseeds and soybeans, are well-known repositories of small molecule chemical components that include isoflavones, sterols, tocopherols, tocotrienols, and lignans. 23, 3537Sesamol, a phenolic component of lignan derivatives, such as sesamin and sesaminol, is generated upon roasting of sesame seeds and during the bleaching process of sesame oil, and it has previously been shown to reduce lipopolysaccharide-induced oxidative stress38and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. 39In the present study, we synthesized a modified form of sesamol (INV-403) and demonstrated that this small molecule markedly inhibited atherosclerosis in a rabbit model, paralleled by a decrease in aortic inflammation oxidative stress and improvement in endothelial function, mediated in part by its effects on inhibition of IKK2 and consequent reduction in nuclear factor-B (NF-B) activation without overt changes in plasma lipid profile in a Watanabe heritable hyperlipidemic (WHHL) model. == Methods == == Animal Model == The Institutional Animal Care and Use Committee at the Ohio State University approved the experimental animal protocols. Ten male MSDC-0602 WHHL rabbits (2 months old) were obtained from the Brown family in MSDC-0602 Odenville, Alabama and allowed to acclimate for 2 weeks before being fed with high-cholesterol chow (fat: 2 . 7%, wt/wt; cholesterol: 0. 5%, wt/wt; Harlan Teklad TD87251) for 6 weeks, at which time point they were randomly assigned to control or INV-403 groups (20 mg/kg per day for 12 weeks). INV-403 was dissolved in 90% ethanol and sprayed onto the high-cholesterol chow. The diet-drug mixture was MSDC-0602 then vacuum dried overnight to remove ethanol and then used to feed rabbits. == Other Methods == Other methods are described in theSupplemental Methods, available online athttp://atvb.ahajournals.org. == Statistics == Results are expressed as meansSD. The unpaired Studentttest was used to compare parameters in the INV-403 and control treated groups. Probability values <0. 05 were reported as significant. With multiple comparisons, a Bonferroni correction was used for multiple comparisons. In vitro experiments comparing INV-403 with other antioxidants involving multiple groups were analyzed using 1-way ANOVA with a Bonferroni post hoc correction. == Results == We first assessed the effect of INV-403 on atherosclerosis in a rabbit model as illustrated inFigure 1A. To enhance the atherosclerosis progression, all rabbits were fed with high-cholesterol chow for a period of 6 weeks before being randomly assigned to the control or INV-403 group. Dietary supplementation with INV-403 started at the end of 6 weeks for a duration of.