Electronegative LDL induces MMP-9 and TIMP-1 release in monocytes through CD14 activation: Inhibitory effect of glycosaminoglycan sulodexide.

Abstract

OBJECTIVE:

Electronegative LDL (LDL(-)) is involved in atherosclerosis through the activation of the TLR4/CD14 inflammatory pathway in monocytes. Matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of metalloproteinase [TIMP]) are also crucially involved in atherosclerosis, but their modulation by LDL(-) has never been investigated. The aim of this study was to examine the ability of LDL(-) to release MMPs and TIMPs in human monocytes and to determine whether sulodexide (SDX), a glycosaminoglycan-based drug, was able to affect their secretion.

APPROACH AND RESULTS:

Native LDL (LDL(+)) and LDL(-) separated by anion-exchange chromatography were added to THP1-CD14 monocytes in the presence or absence of SDX for 24 h. A panel of 9 MMPs and 4 TIMPs was analyzed in cell supernatants with multiplex immunoassays. The gelatinolytic activity of MMP-9 was assessed by gelatin zymography. LDL(-) stimulated the release of MMP-9 (13-fold) and TIMP-1 (4-fold) in THP1-CD14 monocytes, as well as the gelatinolytic activity of MMP-9. Co-incubation of monocytes with LDL(-) and SDX for 24 h significantly reduced both the release of MMP-9 and TIMP-1 and gelatinase activity. In THP1 cells not expressing CD14, no effect of LDL(-) on MMP-9 or TIMP-1 release was observed. The uptake of DiI-labeled LDL(-) was higher than that of DiI-LDL(+) in THP1-CD14 but not in THP1 cells. This increase was inhibited by SDX. Experiments in microtiter wells coated with SDX demonstrated a specific interaction of LDL(-) with SDX.

CONCLUSIONS:

LDL(-) induced the release of MMP-9 and TIMP-1 in monocytes through CD14. SDX affects the ability of LDL(-) to promote TIMP-1 and MMP-9 release by its interaction with LDL(-).

• Authors: Daniela Ligi, Sonia Benitez, Lidia Croce, Andrea Rivas-Urbina, Núria Puig, Jordi Ordóñez-Llanos, Ferdinando Mannello, Jose Luis Sanchez-Quesada
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1864 Issue 12 Pg. 3559-3567 (12 2018) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 30254012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Glycosaminoglycans
• Hypolipidemic Agents
• Lipopolysaccharide Receptors
• Lipoproteins, LDL
• Tissue Inhibitor of Metalloproteinase-1
• glucuronyl glucosamine glycan sulfate
• Matrix Metalloproteinase 9

Topics

• Anti-Inflammatory Agents (pharmacology)
• Cell Line
• Glycosaminoglycans (pharmacology)
• Humans
• Hypolipidemic Agents (pharmacology)
• Lipopolysaccharide Receptors (immunology)
• Lipoproteins, LDL (chemistry, immunology)
• Matrix Metalloproteinase 9 (immunology)
• Monocytes (drug effects, immunology)
• Static Electricity
• Tissue Inhibitor of Metalloproteinase-1 (immunology)