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KR‐31378 ameliorates atherosclerosis by blocking monocyte recruitment in hypercholestrolemic mice
Author(s) -
Kim Jiyun,
Nam KiHoan,
Kim SunOk,
Choi JaeHoon,
Kim HyoungChin,
Yang SungDon,
Kang JooHyoung,
Ryu YoungHan,
Taeg Oh Goo,
Yoo SungEun
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0652fje
Subject(s) - fatty streak , cell adhesion molecule , monocyte , inflammation , chemistry , vcam 1 , cell adhesion , tumor necrosis factor alpha , microbiology and biotechnology , pharmacology , endocrinology , cell , immunology , biology , cholesterol , biochemistry , icam 1
The recruitment of monocytes into the artery wall is a crucial early step in atherogenesis. A novel compound, KR‐31378, has been shown to be a neuroprotective agent for ischemia‐reperfusion damage in rat brain via its potent antioxidant and antiapoptotic actions. Here, we report the effects of this compound on atherogenesis and possible mechanisms of action. In Ldlr knockout mice fed with a high‐fat, high‐cholesterol diet, treatment with KR‐31378 significantly inhibited fatty streak formation and macrophage accumulation. To address the possibility that KR‐31378 may influence the initial stages of atherogenesis, we examined its effect on the adhesion and migration of monocytes to endothelial cells stimulated with tumor necrosis factor‐α. KR‐31378 decreased the adhesion in a dose‐dependent manner. The observed decreases in cell adhesion and migration correlated with KR‐31378‐mediated down‐regulation of vascular cell adhesion molecule‐1 (VCAM‐1) and interleukin (IL)‐8. Nuclear factor‐κB (NF‐κB) is known to regulate the expression of adhesive and chemotactic molecules including VCAM‐1 and IL‐8. Indeed, transient transfection experiments, electrophoretic mobility shift assay, and IκB degradation assay showed that KR‐31378 decreased NF‐κB activation. These results indicate that KR‐31378 potently reduces fatty streak formation by inhibiting NF‐κB‐dependent cellular adhesion and chemotactic molecule expression, which are crucial to monocyte infiltration into the arterial wall during the early stages of atherogenesis.