KR-31543 reduces the production of proinflammatory molecules in human endothelial cells and monocytes and attenuates atherosclerosis in mouse model

Exp Mol Med. 2012 Dec 31;44(12):733-9. doi: 10.3858/emm.2012.44.12.081.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / pathology
  • Atherosclerosis / blood
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / pathology
  • Benzopyrans / pharmacology*
  • Benzopyrans / therapeutic use
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Diet
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Transgenic
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Receptors, CCR2 / metabolism
  • Receptors, LDL / genetics
  • Tetrazoles / pharmacology*
  • Tetrazoles / therapeutic use
  • Transendothelial and Transepithelial Migration / drug effects
  • Triglycerides / blood
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • 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