KR-31543 reduces the production of proinflammatory molecules in human endothelial cells and monocytes and attenuates atherosclerosis in mouse model.
- Author:
Jae Hoon CHOI
1
;
Ji Young YOO
;
Sun Ok KIM
;
Sung Eun YOO
;
Goo Taeg OH
Author Information
1. Laboratory of Molecular Physiology, Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea.
- Publication Type:Research Support, Non-U.S. Gov't ; Original Article
- Keywords:
atherosclerosis;
endothelial cells;
KR-31543;
monocytes;
transendothelial and transepithelial migration
- MeSH:
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
- From:Experimental & Molecular Medicine
2012;44(12):733-739
- CountryRepublic of Korea
- Language:English
-
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.
