Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocytes/macrophages (Mo) appear to play a critical role in the initiation and progression of atherosclerotic lesions. In this study, we characterized in vitro-differentiated embryonic stem (ES) cell macrophages as a model system for studying atherosclerosis-associated Mo functions. Using immunofluorescence staining and Western analysis, we demonstrate that ES Mo express typical macrophage cell surface markers, as well as the known receptors for modified forms of low density lipoprotein (LDL), including the Mo scavenger receptors (SR-A type I and type II), CD36, and CD68. Differentiated ES Mo specifically bind and degrade 125I-labeled acetylated LDL with high affinity, and their incubation with acetylated LDL (15 microg/mL) for 48 hours produces characteristic "foamy" Mo, as visualized by oil red O staining. ES Mo also express matrix-degrading metalloproteinases (MMP-3, MMP-9), which have been implicated in collagen breakdown in the fibrous cap of atherosclerotic plaques, and secrete cytokines (tumor necrosis factor-alpha, interleukin-6) in response to inflammatory stimuli. Transfection experiments, using a green fluorescent protein reporter gene, driven by the myeloid-specific promoter, CD11b, demonstrated that ES Mo can also be used to study macrophage-restricted gene expression in vitro. Taken together, these data demonstrate that ES Mo exhibit many properties typical of arterial lesion macrophages. Its ease of genetic manipulation makes it an attractive system for investigations of macrophage functions in vitro.
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PMID:In vitro-differentiated embryonic stem cell macrophages: a model system for studying atherosclerosis-associated macrophage functions. 976 39

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets.
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PMID:Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. 1800 Sep 63