Role of ADAMTS-1 in Atherosclerosis

Abstract

Objective-We investigated the potential role of ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motif type I) in atherogenesis. Methods and Results-ADAMTS-1 is expressed at the highest levels in the aorta when compared with other human tissues examined. Immunolocalization studies in human aorta and coronary artery indicate that ADAMTS-1 expression is mainly seen at low levels in the medial layer, but upregulated in the intima when plaque is present. We found that ADAMTS-1 mRNA levels are significantly higher in proliferating/migrating cultured primary aortic vascular smooth muscle cells (VSMCs) compared with resting/confluent cells. Using the mouse carotid artery flow cessation model, we show that there are differences in vessel remodeling in ADAMTS-1 transgenic/apoE-deficient mice compared with apoE deficiency alone, particularly a significant increase in intimal hyperplasia. We show that ADAMTS-1 can cleave the large versican containing proteoglycan population purified from cultured human aortic VSMCs. Finally, using versican peptide substrates, we show data suggesting that ADAMTS-1 cleaves versican at multiple sites. Conclusion-We See page 12Early in atherogenesis, VSMCs from the media are thought to migrate into the intima and contribute to the development of atherosclerotic lesions. Although what initially triggers these events is not known, it is thought that proteases released by VSMCs degrade the matrix proteins in the intima, particularly the main proteoglycan of the arterial intima versican, making the intima more permissive for invasion by VSMCs. One recently discovered family of metalloproteases, the ADAMTS family, might play a key role in atherogenesis by modulating the degradation of versican and possibly other proteoglycans.The first member of this family to be identified is ADAMTS-1. 3,4 It has been observed that ADAMTS-1 mRNA is upregulated substantially in human umbilical vein endothelial cells and cardiac microvascular endothelial cells under shear stress, suggesting regulation during flow-dependent vascular remodeling. 5 ADAMTS-1 has been shown to cleave the proteoglycan versican, which is expressed by VSMCs. 6 -8 Versican can exist in 4 isoforms (V0, V1, V2, and V3), depending on alternative splicing of the chondroitin sulfate containing glycosaminoglycan domains. V0 versican contains all possible domains, whereas the glycosaminoglycan-alpha and glycosaminoglycan-beta domains are spliced out in the V1 and V2 versican isoforms, respectively. 7 ADAMTS-1 and ADAMTS-4 have been shown to cleave V1/V0 versican at the Glu 441 -Ala 442 /Glu 1428 -Ala 1429 bond and the product of this cleavage was shown to be present in human atherosclerotic plaques by immunohistochemistry using neoepitope antibodies. 8 ADAMTS-1 has also been shown to have a role in matrix remodeling during ovulation in mice, which involves dissolution of connective matrix and cellular layers. A. ADAMTS-1-deficient mice displayed impaired ovulation, and the authors proposed that this was at least partially caused by...

Extracellular matrix of the central nervous system: from neglect to challenge

“…Five ADAMTS sites have been characterized in the aggrecan core protein (Caterson et al 2000;Lemons et al 2001), two to four in the proteoglycan isoforms of versican (V2-V0) (Jonsson-Rylander et al 2005;Sandy et al 2001;Westling et al 2004) and one in brevican (Matthews et al 2000;Yamada et al 1995). Interestingly, in all of these lecticans one ADAMTS-site is located next to the globular G1-domain allowing the selective release of the large GAG-carrying portions from the complex with hyaluronan and link proteins.…”

Versican Degradation and Vascular Disease

“…Plasmin has been shown to degrade native versican in vitro . Finally, ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-1 (Sandy et al 2001, Jonsson-Rylander et al 2005, -4 (Sandy et al 2001), -5 (unpublished observations in Cross et al;Cross et al 2005), and -9 (Somerville et al 2003) have been reported to cleave either native versican or versican peptide substrates, whereas ADAMTS-8 and -15 are candidates based on sequence similarity (Nicholson et al 2005). …”

“…The 70-kDa G1 fragment of versican formed by ADAMTS activity at the Glu 441 -Ala 442 bond of V1 has been documented (Sandy et al 2001), whereas other potential ADAMTS cleavage sites, such as Tyr 423 -Ile 424 of V1, have been proposed based on activity against peptide substrates (Jonsson-Rylander et al 2005). There is increasing evidence for the role of ADAMTS enzymes in the catabolic modification of versican, but further work is necessary to characterize the complete panel of proteolytic enzymes involved in versican cleavage in vascular tissue and their activation patterns in the various forms and stages of vascular pathologies.…”

“…Ig, Immunoglobulin-like domain; HABR, hyaluronan binding region; αGAG, α glycosaminoglycan binding domain; βGAG, β glycosaminoglycan binding domain; EGF, EGF-like domain; LC, C-type lectin domain; CRP, complement regulatory protein-like domain. The cleavage at Glu 441 -Ala 442 (green asterisk) has been documented in vivo (Sandy et al 2001), whereas potential cleavage by ADAMTS1 at Tyr 423 -Ile 424 (red asterisk) has been reported (Jonsson-Rylander et al 2005).…”

ADAMTS-7 promotes vascular smooth muscle cells proliferation in vitro and in vivo

“…Recently, the role of ADAMTS proteases in inflammation and atherosclerosis has come to light [25]. Jonsson-Rylander and colleagues [26] reported that ADAMTS-1 might expedite atherogenesis by cleaving the ECM protein versican. The 227 Pro polymorphism in ADAMTS-1 was associated with a nearly twofold increased risk of coronary heart disease event [27].…”