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: Jae-Hoon Choi, Ji-Young Yoo, Sun-Ok Kim, Sung-Eun Yoo, Goo Taeg Oh
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 44 Issue 12 Pg. 733-9 (Dec 31 2012) ISSN: 2092-6413 [Electronic] United States
• PMID: 23143639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzopyrans
• CCR2 protein, human
• CXCL8 protein, human
• Cholesterol, HDL
• Cholesterol, LDL
• IL6 protein, human
• Inflammation Mediators
• Interleukin-6
• Interleukin-8
• KR-31543
• Neuroprotective Agents
• Receptors, CCR2
• Receptors, LDL
• Tetrazoles
• Triglycerides
• Vascular Cell Adhesion Molecule-1

Topics

• 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)