Related Experiment Video
Updated: Mar 19, 2026
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Oxidized LDL-Exposed Human Macrophages Display Increased MMP-9 Expression and Secretion Mediated by Endoplasmic
Gabriela M Sanda1, Mariana Deleanu1,2, Laura Toma1
1Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
Abstract:
Oxidatively modified low-density lipoproteins (oxLDL) alter the proper function of the endoplasmic reticulum (ER), inducing ER stress (ERS), which consequently activates inflammatory pathways in macrophages. Matrix metalloproteinase-9 (MMP-9) is the main protease acting on the degradation of the extracellular matrix and the ensuing destabilization of the atherosclerotic plaque. We aimed to investigate whether ERS induced by oxLDL or tunicamycin (TM) in human macrophages is associated with the stimulation of MMP-9 expression and secretion. The results showed that oxLDL induced in THP-1 macrophages: (i) increase of MMP-9 gene expression and its pro-form secretion, (ii) intracellular accumulation of 7-ketocholesterol, (iii) ERS activation (increased eIF2α phosphorylation, XBP1 and CHOP mRNA levels, and Grp78 protein expression), and (iv) oxidative stress (increased levels of reactive oxygen species and NADPH oxidase activity). Incubation of macrophages with ERS inducer, TM determined the secretion of both pro- and active-form of MMP-9 and oxidative stress. Treatment of oxLDL or TM-incubated cells with ERS inhibitor, sodium phenylbutyrate decreased MMP-9 gene expression, secretion, and activity. The inhibitor of NADPH oxidase, apocynin, decreased XBP-1 and CHOP mRNA levels, and MMP-9 gene expression and secretion in oxLDL-exposed cells. In conclusion, oxLDL stimulate MMP-9 expression and secretion in human macrophages by mechanisms involving ERS. J. Cell. Biochem. 118: 661-669, 2017. © 2016 Wiley Periodicals, Inc.
Insights
Oxidatively modified LDL induces endoplasmic reticulum stress in macrophages, increasing MMP-9 expression and secretion, contributing to atherosclerotic plaque instability.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Oxidatively modified low-density lipoproteins (oxLDL) disrupt endoplasmic reticulum (ER) function, leading to ER stress (ERS) and activating inflammatory pathways.
- Matrix metalloproteinase-9 (MMP-9) plays a critical role in extracellular matrix degradation and atherosclerotic plaque destabilization.
Purpose of the Study:
- To investigate the association between oxLDL- or tunicamycin (TM)-induced ERS and the stimulation of MMP-9 expression and secretion in human macrophages.
- To elucidate the underlying mechanisms involving oxidative stress and ERS in oxLDL-mediated MMP-9 regulation.
Main Methods:
- THP-1 macrophages were exposed to oxLDL or TM to induce ERS and oxidative stress.
- MMP-9 expression, secretion, and activity were assessed using various molecular and biochemical assays.
- ERS markers (eIF2α phosphorylation, XBP1, CHOP, Grp78) and oxidative stress markers (ROS, NADPH oxidase activity) were quantified.
- Pharmacological inhibitors of ERS (sodium phenylbutyrate) and NADPH oxidase (apocynin) were used to determine their effects on MMP-9 regulation.
Main Results:
- oxLDL induced MMP-9 gene expression and pro-form secretion, intracellular 7-ketocholesterol accumulation, ERS activation, and oxidative stress in macrophages.
- TM also induced MMP-9 secretion and oxidative stress.
- ERS inhibition significantly reduced MMP-9 expression, secretion, and activity.
- NADPH oxidase inhibition attenuated ERS markers and MMP-9 expression and secretion in oxLDL-exposed cells.
Conclusions:
- oxLDL stimulates MMP-9 expression and secretion in human macrophages through mechanisms involving ERS.
- ERS and oxidative stress are key mediators in the regulation of MMP-9 by oxLDL in macrophages.
- Targeting ERS and oxidative stress pathways may offer therapeutic strategies for managing atherosclerotic plaque instability.
