ADAM and ADAMTS disintegrin and metalloproteinases as major factors and molecular targets in vascular malfunction and disease.

Abstract

A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic enzymes. ADAMs are largely membrane-bound enzymes that act as molecular scissors or sheddases of membrane-bound proteins, growth factors, cytokines, receptors and ligands, whereas ADAMTS are mainly secreted enzymes. ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and transmembrane domain. Similarly, ADAMTS family members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but instead of a transmembrane domain they have thrombospondin motifs. Most ADAMs and ADAMTS are activated by pro-protein convertases, and can be regulated by G-protein coupled receptor agonists, Ca2+ ionophores and protein kinase C. Activated ADAMs and ADAMTS participate in numerous vascular processes including angiogenesis, vascular smooth muscle cell proliferation and migration, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs and ADAMTS also play a role in vascular malfunction and cardiovascular diseases such as hypertension, atherosclerosis, coronary artery disease, myocardial infarction, heart failure, peripheral artery disease, and vascular aneurysm. Decreased ADAMTS13 is involved in thrombotic thrombocytopenic purpura and microangiopathies. The activity of ADAMs and ADAMTS can be regulated by endogenous tissue inhibitors of metalloproteinases and other synthetic small molecule inhibitors. ADAMs and ADAMTS can be used as diagnostic biomarkers and molecular targets in cardiovascular disease, and modulators of ADAMs and ADAMTS activity may provide potential new approaches for the management of cardiovascular disorders.