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

Although statin therapy is a cornerstone of current low density lipoprotein (LDL)-lowering strategies, there is a need for additional therapies to incrementally lower plasma LDL cholesterol. In this study, we investigated the effect of several methylenedioxyphenol derivatives in regulating LDL cholesterol through induction of LDL receptor (LDLR). INV-403, a modified methylenedioxyphenol derivative, increased LDLR mRNA and protein expression in HepG2 cells in a dose- and time-dependent fashion. These effects were apparent even under conditions of HMG-CoA reductase inhibition. Electrophoresis migration shift assays demonstrated that INV-403 activates SREBP2 but not SREBP1c, with immunoblot analysis showing an increased expression of the mature form of SREBP2. Knockdown of SREBP2 reduced the effect of INV-403 on LDLR expression. The activation of SREBP2 by INV-403 is partly mediated by Akt/GSK3ß pathways through inhibition of phosphorylation-dependent degradation by ubiquitin-proteosome pathway. Treatment of C57Bl/6j mice with INV-403 for two weeks increased hepatic SREBP2 levels (mature form) and upregulated LDLR with concomitant lowering of plasma LDL levels. Transient expression of a LDLR promoter-reporter construct, a SRE-mutant LDLR promoter construct, and a SRE-only construct in HepG2 cells revealed an effect predominantly through a SRE-dependent mechanism. INV-403 lowered plasma LDL cholesterol levels through LDLR upregulation. These results indicate a role for small molecule approaches other than statins for lowering LDL cholesterol.

A modified sesamol derivative inhibits progression of atherosclerosis.

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). CONCLUSIONS: INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor-κB signaling.