on May 9, 2002
Published online before print May 9, 2002, doi: 10.1161/01.ATV.0000021411.53577.1C
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Submitted on March 5, 2002
Accepted on April 26, 2002
Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma
Terry C. Major *;
From the Cardiovascular Pharmacology, Pfizer Global Research & Development, Pfizer, Inc, Ann Arbor, Mich.
* To whom correspondence should be addressed. E-mail: terry.major{at}pfizer.com.
Objective—Because extracellular matrix metalloproteinase inducer (EMMPRIN), a tumor cell--derived protein, induces matrix metalloproteinases (MMPs) in fibroblasts and because MMPs are important in atheroma formation, we investigated if EMMPRIN was expressed in granulocyte/macrophage-colony stimulating factor (GM-CSF)--differentiated human peripheral blood monocytes (HPBM) and macrophage foam cells. In addition, EMMPRIN was studied for its expression in human atheroma.
Methods and Results—After 10 days of GM-CSF--induced monocyte differentiation, EMMPRIN mRNA increased 5- to 8-fold relative to undifferentiated monocytes. GM-CSF treatment of HPBM revealed that both EMMPRIN mRNA and protein were upregulated by day 2 over undifferentiated monocytes. GM-CSF--differentiated HPBM showed characteristic macrophage phenotype by showing increases in pancake-like morphology and increases in biochemical markers such as apolipoprotein E, MMP-9, and cholesterol ester (CE). While acetylated LDL treatment of the 10-day GM-CSF--differentiated HPBM increased CE mass 13- to 321-fold, EMMPRIN expression was unchanged relative to nonlipid-loaded macrophages. In human coronary atherosclerotic samples, EMMPRIN was observed in CD68(+) macrophage-rich areas as well as areas of MMP-9 expressions.
Conclusions—Based on these data, we conclude that monocyte differentiation induces EMMPRIN expression, CE enrichment of foam cells has no further effect on EMMPRIN expression, and EMMPRIN is present in human atheroma. Therefore, EMMPRIN may play a role in atherosclerosis development.
Key words: atherosclerosis • EMMPRIN (extracellular matrix metalloproteinase inducer) • cholesterol ester • human peripheral blood monocyte (HPBM) • matrix metalloproteinase-9 (MMP-9) • matrix metalloproteinase-1 (MMP-1)
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