title: KR-31378 ameliorates atherosclerosis by blocking monocyte recruitment in hypercholestrolemic mice.
abstract: 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-alpha. 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-kappaB (NF-kappaB) 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 IkappaB degradation assay showed that KR-31378 decreased NF-kappaB activation. These results indicate that KR-31378 potently reduces fatty streak formation by inhibiting NF-kappaB-dependent cellular adhesion and chemotactic molecule expression, which are crucial to monocyte infiltration into the arterial wall during the early stages of atherogenesis.
authors.affiliation: Laboratory of Development and Differentiation, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon, Korea.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Kim
authors.forename: Ki-Hoan
authors.initials: KH
authors.lastname: Nam
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Hyoung-Chin
authors.initials: HC
authors.lastname: Kim
authors.forename: Sung-Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Joo-Hyoung
authors.initials: JH
authors.lastname: Kang
authors.forename: Young-Han
authors.initials: YH
authors.lastname: Ryu
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D004036:Diet, Atherogenic; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D002630:Chemotactic Factors; D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D016328:NF-kappa B; D011714:Pyrans; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1