title: 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.
  
  
  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.
authors.affiliation: Davis Heart Lung Research Institute, Ohio State University, Columbus, OH 43210-1252, USA.
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Nisharahmed
authors.initials: N
authors.lastname: Kherada
authors.forename: Thomas
authors.initials: T
authors.lastname: Kampfrath
authors.forename: Georgeta
authors.initials: G
authors.lastname: Mihai
authors.forename: Orlando
authors.initials: O
authors.lastname: Simonetti
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Desikan
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Ouiliana
authors.initials: O
authors.lastname: Ziouzenkova
authors.forename: Sampath
authors.initials: S
authors.lastname: Parthasarathy
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D052117:Benzodioxoles / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D011817:Rabbits; D013997:Time Factors; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D052117:Benzodioxoles; D002317:Cardiovascular Agents; D015815:Cell Adhesion Molecules; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010636:Phenols; D000072000:NF-KappaB Inhibitor alpha; C025583:sesamol; D051550:I-kappa B Kinase