A Modified Sesamol Derivative Inhibits Progression of Atherosclerosis

Abstract

Objective Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis. Methods and Results Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 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 factor–κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2). Conclusion INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor–κB signaling.

Modified methylenedioxyphenol analogs lower LDL cholesterol through induction of LDL receptor expression

“…We previously showed that INV-403 had no LDL-lowering effects in LDLR-deficient WHHL rabbits ( 15 ). Consistent with this data, our current study, while demonstrating an effect of LDL lowering in wild-type mice, was unable to discern an effect on LDL lowering in LDLR Ϫ / Ϫ mice, indicating that LDLR may be essential for the LDL-lowering action of INV-403.…”

“…Target proteins were detected by primary antibodies as follows: mouse anti-␤ -actin LDLR ( 14 ). We previously synthesized an analog of methylenedioxyphenol (MDP), INV-403, and we demonstrated that, in a model of LDLR defi ciency, this small molecule inhibited atherosclerosis, paralleled by a decrease in aortic infl ammation oxidative stress and improvement in endothelial function without overt change in plasma lipid profi le and LDL ( 15 ). In the present study, we assess the effects of INV-403 and related analogs on cholesterol metabolism and LDLR expression, and we show that treatment with INV-403 unexpectedly and dramatically reduced plasma LDL, paralleled by an increase in the hepatic LDLR.…”

Attenuation of adjuvant-induced arthritis by dietary sesamol via modulation of inflammatory mediators, extracellular matrix degrading enzymes and antioxidant status

“…Similarly, MMP-13, -3, -1 and -9 are significantly higher in synovial fluids and serum of arthritic patients [3]. The MMP-mediated fibronectin degradative products are found to amplify cartilage degeneration, as they in turn activate MMPs and other inflammatory signals [7,29]. Thus, inhibition of HAase and MMPs is considered as a prime target to prevent disease perpetuation.…”

“…Sesamol (3, 4-methylenedioxyphenol) is one of the known phenolic antioxidant found in the sesame seed and has been shown to possess cardio-protective, hepato-protective, chemopreventive, anti-inflammatory, anti-diabetic, anti-atherogenic, and anti-aging properties. Lately, sesamol has been demonstrated to quench oxidative-nitrosative stress and inflammation by inhibiting NF-jB and IjB kinase (IKK) activation pathways [6,7]. Since arthritis is associated with secondary complications such as cardiovascular disorders and diabetes [8], it would be interesting to have a molecule that can prevent arthritis as well as oxidative stress-induced pathologies.…”

Nicotine Induces Pro-inflammatory Response in Aortic Vascular Smooth Muscle Cells Through a NFκB/Osteopontin Amplification Loop-Dependent Pathway

“…Numerous inflammatory mediators, cell adhesion molecules, and cytokines were regulated by NFκB [20,21]. Thus, its activation has been considered as a hallmark of inflammation and was considered as a therapeutic target for atherosclerosis [22] and aortic aneurysm [23]. In our study, the heterodimers of p65/ p50 were activated and IL-6 and MCP-1 expressions were upregulated substantially.…”