Abstract
The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular matrix and blood. The best characterized cardiovascular role is that of ADAMTS-13 in blood. Moderately low ADAMTS-13 levels increase the risk of ischeamic stroke and very low levels (less than 10%) can cause thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 is currently in clinical trials for treatment of TTP. Recently, new cardiovascular roles for ADAMTS proteases have been discovered. Several ADAMTS family members are important in the development of blood vessels and the heart, especially the valves. A number of studies have also investigated the potential role of ADAMTS-1, -4 and -5 in cardiovascular disease. They cleave proteoglycans such as versican, which represent major structural components of the arteries. ADAMTS-7 and -8 are attracting considerable interest owing to their implication in atherosclerosis and pulmonary arterial hypertension, respectively. Mutations in the ADAMTS19 gene cause progressive heart valve disease and missense variants in ADAMTS6 are associated with cardiac conduction. In this review, we discuss in detail the evidence for these and other cardiovascular roles of ADAMTS family members, their proteolytic substrates and the potential molecular mechanisms involved.
Highlights
The extracellular matrix (ECM) guides the formation of cardiovascular tissues during embryogenesis and supports it throughout adulthood by providing structural support, guidance of cell behaviour and sequestering of growth factors
Whereas non-cardiovascular roles of the different a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family members have been discussed in recent excellent reviews [10,14], here, we will discuss in detail the involvement of ADAMTS proteases in cardiovascular biology and disease
Expression of versican is essential for normal development of heart and blood vessels [45,46].Versican is involved in various aspects of vascular lesion development and is present in atherosclerotic plaques, restenotic lesions, lesions arising during graft repair and aneurysmal lesions [27].Versican levels increase dramatically in atherosclerosis [27,47], suggesting that its accumulation may in part be responsible for increased low-density lipoprotein (LDL) deposition/internalization in the vessel wall
Summary
The extracellular matrix (ECM) guides the formation of cardiovascular tissues during embryogenesis and supports it throughout adulthood by providing structural support, guidance of cell behaviour and sequestering of growth factors. The ratios of PGs and the interspersed collagens/elastic fibres provide a means of balance between stiffness and flexibility of the cardiovascular tissues [7] For this reason, remodelling of the vascular ECM by proteases secreted by both ECs and VSMCs is crucial to establish the mechanical properties of these tissues. Proteases of the related family of a disintegrin and metalloproteinases (ADAMs) exert a fundamental role in the vascular ECM owing to their ability to selectively cleave the ectodomain of membrane proteins (shedding). The role of these metalloproteinase families in cardiovascular disorders has been exhaustively reviewed elsewhere [8,9]. Whereas non-cardiovascular roles of the different ADAMTS family members have been discussed in recent excellent reviews [10,14], here, we will discuss in detail the involvement of ADAMTS proteases in cardiovascular biology and disease
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