Exp Mol Med.
2012 Dec;44(12):733-739.
KR-31543 reduces the production of proinflammatory molecules in human endothelial cells and monocytes and attenuates atherosclerosis in mouse model
- Affiliations
-
- 1Laboratory of Molecular Physiology, Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea.
- 2Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea. gootaeg@ewha.ac.kr
- 3Samyang Corporation, Daejeon 305-717, Korea.
- 4Graduate School of New Drug Discovery and Development, Chungnam National University, Daejon 305-764, Korea.
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 ischemia-reperfusion 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.
Keyword
MeSH Terms
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Animals
Aorta/pathology
Atherosclerosis/blood/*drug therapy/pathology
Benzopyrans/*pharmacology/therapeutic use
Cholesterol, HDL/blood
Cholesterol, LDL/blood
Diet
Disease Models, Animal
Human Umbilical Vein Endothelial Cells/drug effects/metabolism
Inflammation Mediators/*metabolism
Interleukin-6/metabolism
Interleukin-8/metabolism
Macrophages/metabolism
Mice
Mice, Transgenic
Monocytes/drug effects/*metabolism
Neuroprotective Agents/*pharmacology/therapeutic use
Receptors, CCR2/metabolism
Receptors, LDL/genetics
Tetrazoles/*pharmacology/therapeutic use
Transendothelial and Transepithelial Migration/drug effects
Triglycerides/blood
Vascular Cell Adhesion Molecule-1/metabolism
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