title: KR-31543 reduces the production of proinflammatory molecules in human endothelial cells and monocytes and attenuates atherosclerosis in mouse model.
abstract: KR-31543, (2S, 3R, 4S)-6-amino-4-[N-(4-chlorophenyl)- N-(2-methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro- 2-dimethyoxymethyl-3-hydroxy-2-methyl-2H-1-benz opyran is a new neuroprotective agent for ischemiareperfusion damage. It has also been reported that KR-31543 has protective effects on lipid peroxidation and H₂O₂-induced reactive oxygen species production. In this study, we investigated the anti-inflammatory and anti-atherogenic properties of KR-31543. We observed that KR-31543 treatment reduced the production of MCP-1, IL-8, and VCAM-1 in HUVECs, and of MCP-1 and IL-6 in THP-1 human monocytes. We also examined the effect of KR-31543 on monocytes migration in vitro. KR-31543 treatment effectively reduced the migration of THP-1 human monocytes to the HUVEC monolayer in a dose-dependent manner. We next examined the effects of this compound on atherogenesis in LDL receptor deficient (Ldlr ⁻/⁻) mice. After 10 weeks of western diet, the formation of atherosclerotic lesion in aorta was reduced in the KR-31543-treated group compared to the control group. The accumulation of macrophages in lesion was also reduced in KR-31543 treated group. However, the plasma levels of total cholesterol, HDL, LDL, and triglyceride were not affected by KR-31543 treatment. Taken together, these results show that KR-31543 has anti-inflammatory properties on human monocytes and endothelial cells, and inhibits fatty streak lesion formation in mouse model of atherosclerosis, suggesting the potential of KR-31543 for the treatment for atherosclerosis.
authors.affiliation: Laboratory of Molecular Physiology, Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Kore.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004032:Diet; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D054390:Receptors, CCR2 / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001578:Benzopyrans; C515334:CCR2 protein, human; C508606:CXCL8 protein, human; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; C473251:KR-31543; D018696:Neuroprotective Agents; D054390:Receptors, CCR2; D011973:Receptors, LDL; D013777:Tetrazoles; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1