title: ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques.
abstract: OBJECTIVE
  Remodeling of extracellular matrix (ECM) plays an important role in inflammatory disorders such as atherosclerosis. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently described family of proteinases that is able to degrade the ECM proteins aggrecan and versican expressed in blood vessels. The purpose of the present study was to analyze the expression and regulation of several ADAMTSs before and after macrophage differentiation and after stimulation with IFN-gamma, IL-1beta and TNF-alpha. ADAMTS expression was also examined during atherosclerosis development in mice and in human atherosclerotic plaques.
  
  
  RESULTS
  Real time RTPCR showed that, of the nine different ADAMTS members examined, only ADAMTS-4 and -8 were induced during monocyte to macrophage differentiation, which was also seen at protein level. Macrophage expression of ADAMTS-4, -7, -8 and -9 mRNA were enhanced upon stimulation with IFN-gamma or TNF-alpha. Furthermore, immunohistochemical analyses revealed that ADAMTS-4 and -8 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. In addition, ADAMTS-4 expression was upregulated during the development of atherosclerosis in LDLR(-/-)ApoB(100/100) mice. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas, it was significantly higher in aortas from 30-40-week old atherosclerotic animals.
  
  
  CONCLUSIONS
  The present study suggests that ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques. This is the first study associating ADAMTS-4 and -8 expression with atherosclerosis. However, further experiments are required to understand the physiological and pathological functions of ADAMTS in the vascular wall, and tools to measure ADAMTS activity need to be developed.
authors.affiliation: Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden. Dick.Wagsater@ki.se
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
authors.forename: Hanna
authors.initials: H
authors.lastname: Björk
authors.forename: Chaoyong
authors.initials: C
authors.lastname: Zhu
authors.forename: Johan
authors.initials: J
authors.lastname: Björkegren
authors.forename: Guro
authors.initials: G
authors.lastname: Valen
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis*; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology; D011348:Procollagen N-Endopeptidase / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C120807:ADAMTS8 protein, human; C498472:Adamts8 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse