Abstract 10735: Novel Role of ADAMTS-5 in Proteoglycan Degradation in Atherosclerosis
Atherosclerosis is caused by retention of atherogenic lipoproteins on vascular proteoglycans. A proteomics comparison of atherosclerotic aortas from apolipoprotein E-deficient (apoE-/-) and wildtype mice revealed that proatherogenic proteoglycans, such as biglycan and versican, were increased alongside proteoglycans with less known functions in the vasculature such as aggrecan and asporin. Yet, their expression at the transcript level was unchanged. This prompted us to investigate whether proteoglycan accumulation is the result of reduced catabolism, and we focused on a recently discovered proteoglycanase, which targets aggrecan in cartilage tissues, ADAMTS-5 (A Disintegrin And Metalloproteinase with Thrombospondin motifS). We report here for the first time that ADAMTS-5 is expressed in the murine and human vasculature. Most importantly, ADAMTS-5 levels were reduced in the atherosclerotic apoE-/- aortas. Proteomics analysis confirmed that the enzyme is capable of cleaving vascular versican, aggrecan and biglycan and induced the release of ADAMTS-specific versican and aggrecan fragments as well as hyaladherins from the aortic wall. Immunohistochemical staining showed that the versican fragments colocalized with apolipoprotein B in advanced atherosclerotic lesions, suggesting that proteolytic processing of versican by ADAMTS-5 may affect its interaction with lipoproteins. In vitro experiments confirmed the expression of ADAMTS-5 by aortic smooth muscle cells (SMCs) and by cultured aortic explants. Stimulation with fibroblast growth factor 2 (FGF-2) reduced ADAMTS-5 expression in SMCs and blocked the release of ADAMTS-generated versican fragments from cultured aortic explants. Finally, the presence of ADAMTS-5 was confirmed in human carotid endarterectomy lesions. In conclusion, this study is the first to implicate ADAMTS-5 in atherosclerosis, suggesting that reduced expression of this catabolic enzyme could result in decreased proteoglycan turnover and retention of proatherogenic lipoproteins in the vasculature.
- © 2011 by American Heart Association, Inc.