Davis Heart Lung Research Institute, Ohio State University, Columbus, OH 43210-1252, USA.
Arterioscler Thromb Vasc Biol. 2011 Mar;31(3):536-42. doi: 10.1161/ATVBAHA.110.219287. Epub 2010 Dec 23.
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.
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).
INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor-κB signaling.
芝麻酚是木脂素的一种酚类成分，先前已被证明可减轻脂多糖诱导的氧化应激，并上调磷脂酰肌醇 3-激酶/蛋白激酶 B/内皮型一氧化氮合酶通路。本研究合成了芝麻酚的一种改良形式（INV-403）以增强其特性，并评估其对动脉粥样硬化的影响。
给予 Watanabe 遗传性高脂血症兔高胆固醇饮食 6 周，然后随机分为单独给予高胆固醇饮食或联合给予 INV-403（每天 20mg/kg）治疗 12 周。连续 MRI 分析表明 INV-403 可迅速减少动脉粥样硬化斑块（6 周内），12 周治疗后形态学分析证实，动脉粥样硬化减少伴随着脂质和炎症细胞含量减少。与 INV-403 对动脉粥样硬化的影响一致，它改善了血管功能（减少血管紧张素 II 引起的收缩和增加乙酰胆碱引起的舒张），降低了全身和斑块氧化应激，并通过抑制核因子-κB 激活来抑制核因子 κB 激活，从而抑制核因子 κB 激活κB 轻链增强子的 B 细胞抑制剂，α（IκBα）磷酸化，同时协调减少关键内皮黏附分子。在培养的内皮细胞的体外实验中，发现 INV-403 通过抑制 IκB 激酶 2（IKK2）来减少 IκBα 磷酸化。
INV-403 是一种新型改良木脂素衍生物，通过其对 IKK2 和核因子-κB 信号的作用，可有效抑制动脉粥样硬化的进展。
