ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques

Wågsäter, Dick; Björk, Hanna; Zhu, Chaoyong; Björkegren, Johan; Valen, Guro; Hamsten, Anders; Eriksson, Per

doi:10.1016/j.atherosclerosis.2007.05.018

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Volume 196, Issue 2 , Pages 514-522, February 2008

ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques

Dick Wågsäter
- Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
- These authors contributed equally to the work.
- Corresponding author at: King Gustaf V Research Institute, Building M1, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden. Tel.: +46 8 51770321; fax: +46 8 311298.
Hanna Björk
- Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
- These authors contributed equally to the work.
Chaoyong Zhu
- Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
Johan Björkegren
- Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
Guro Valen
- Department of Basic Medical Science, Department of Physiology, University of Oslo, Oslo, Norway
Anders Hamsten
- Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
Per Eriksson
- Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden

Received 27 February 2007; received in revised form 10 May 2007; accepted 14 May 2007. published online 09 July 2007.

Abstract

Objectives

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-γ, IL-1β and TNF-α. ADAMTS expression was also examined during atherosclerosis development in mice and in human atherosclerotic plaques.

Methods and 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-γ or TNF-α. 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.

Conclusion

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.

Keywords: ADAMTS, Atherosclerosis, Inflammation, Macrophages, Matrix-degrading proteases