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).

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: Zhekang Ying, Nisharahmed Kherada, Thomas Kampfrath, Georgeta Mihai, Orlando Simonetti, Rajagopal Desikan, Karuppaiyah Selvendiran, Qinghua Sun, Ouiliana Ziouzenkova, Sampath Parthasarathy, Sanjay Rajagopalan
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 3 Pg. 536-42 (Mar 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21183734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzodioxoles
• Cardiovascular Agents
• Cell Adhesion Molecules
• I-kappa B Proteins
• NF-kappa B
• Phenols
• NF-KappaB Inhibitor alpha
• sesamol
• I-kappa B Kinase

Topics

• Animals
• Aorta (drug effects, metabolism, pathology, physiopathology)
• Aortic Diseases (genetics, metabolism, pathology, physiopathology, prevention & control)
• Atherosclerosis (genetics, metabolism, pathology, physiopathology, prevention & control)
• Benzodioxoles (pharmacology)
• Cardiovascular Agents (pharmacology)
• Cattle
• Cell Adhesion Molecules (genetics, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, metabolism)
• Gene Expression Regulation
• Hyperlipidemias (drug therapy, genetics, metabolism, pathology, physiopathology)
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• I-kappa B Proteins (metabolism)
• Magnetic Resonance Imaging
• Male
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Phenols (pharmacology)
• Phosphorylation
• Rabbits
• Time Factors
• Transfection
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)