ADAMTS 7 in Cardiovascular Disease : From Bedside to Bench and Back Again ? Running title :

1 Laboratory of Matrix Metalloproteinases in Angiogenesis and Inflammation; 2 2 La L b boratory of f Mo Mole le ecu cu c la ar r r an and d d Ge Ge G netic Cardiovascular Pathoph ph phys y y iology, Vascular B B Bio io iology Program, Centro Na aci ci ion on onal al al d de e e In In Inve ve vest st stig ig gac ac acio io ione ne nes s s Ca Ca Card rdio io iova va v sc s u u ula a ares s s C C Car ar arlo lo los s II II III I (C (C (CNI NI NIC) C) C , Ma Ma Madr dr drid id id, , Sp Sp pai ai ain n n Ad ddr dres ess s f fo for r Co Corr res espo p d nd nde ence ce: : 2 Metzincins, a family of zinc metalloproteinases able to process all the extracellular matrix (ECM) components, include the matrix metalloprotease (MMP), a disintegrin and metalloproteinase (ADAM), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) subfamilies. Metzincins are important regulators of tissue remodeling, particularly vascular remodeling during atherosclerosis development. 1 In the atherosclerotic artery wall these enzymes cause profound alterations to the ECM, and these alterations instigate changes in the behavior of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). 2 Recent genome-wide association (GWA) studies have identified ADAMTS7 as a novel locus associated with human coronary atherosclerosis. 3, 4 However, a causal link between this secreted zinc metalloprotease and atherosclerosis has yet to be established. In this issue of Circulation, Bauer and colleagues 5 directly address this hypothesis by generating whole-body knockout mice for Adamts7 for the investigation of atherosclerosis development. The authors crossed Adamts7-null mice with the atherosusceptible apoE-KO and Ldlr-KO mouse models and found that deletion of Adamts7 significantly reduced atherosclerotic lesion formation in the aortas and aortic roots of both hyperlipidemic strains. The atheroprotective effect of Adamts7 deletion occurred without significant changes in plasma lipid levels or plaque composition, and was associated with impeded migration of Adamts7-null VSMCs in response to TNFD. The early and transient upregulation of Adamts7 in the plaques of atheroprone mice suggests that Adamts7 makes an important contribution at early stages of the disease. However, mouse models are of limited use for the analysis of late atherosclerotic and thrombotic events, …