DOI: 10.1161/CIRCULATIONAHA.115.015711
ADAMTS7 in Cardiovascular Disease: From Bedside to Bench and Back Again?
Running title: Arroyo et al.; Role of ADAMTS7 in vascular remodeling
Alicia G. Arroyo, MD, PhD1; Vicente Andrés, PhD2
1
Laboratory of Matrix Metalloproteinases in Angiogenesis and Inflammation; 2La Laboratory L boratory off
Mole Mo leecu c laar an andd Ge G netic Cardiovascular Pathoph phys ph y iology, Vascular B iology Program, Centro io Molecular Genetic Pathophysiology, Biology Nacional Naaciion onal al de de Investigaciones Inve In vest ve stig st ig gac acio ione io ness Cardiovasculares ne Card Ca rdio iova io v sc va s ulaaress C Carlos arlo ar loss II lo IIII (C (CNI (CNIC), NIC) NI C , Ma C) Madr Madrid, drid dr id,, Sp id Spain pai ainn
Address Ad ddr dres esss for for Correspondence: Corrres Co espo p nd nde dence ce:: Vicente Andrés, Andr drés dr és,, Ph és PhD D CNIC Melchor Fernández Almagro 3 28029 Madrid (Spain) Tel: +34-91 453 12 00 (Ext. 1502) Fax: +34-91 453 12 65 E-mail: [email protected]
Journal Subject Codes: Atherosclerosis:[89] Genetics of cardiovascular disease, Atherosclerosis:[145] Genetically altered mice, Atherosclerosis:[141] Functional genomics, Vascular biology:[96] Mechanism of atherosclerosis/growth factors Key words: ADAMTS7, COMP1, TSP-1, Editorial, matrix metalloproteinases, atherosclerosis, endothelialization, smooth muscle
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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, 4However, a causal link between this secreted zinc metalloprotease and atherosclerosis has yet to be established. In this issue of Circulation, Bauer and colleagues5 directly address this hypothesis by gene ge nera ne raati ting ngg whole-body whole lee-b -bod o y knock-out mice for Adam mts ts77 for the investigation invessti t gati tiion of atherosclerosis generating Adamts7 ddevelopment. dev evelopment. ve T The he aut authors utho hoors ccrossed rossed ros ssed d Adam Adamts7-null A dam amts7--nu -null mice mi with wit ithh the th he atherosusceptible athhero rossuscep pti tibble ble ap aapoE-KO oE--KO and oE and nd Ld Ldlr-KO dlr lr-K -KO -K O mo mou mouse use mo use mode models deels aand nd ffound ou und tthat hatt de ha dele deletion lettion le on ooff Ad Adam Adamts7 amts am ts77 ssignificantly ts ignnifi ig nifiica cant nttly y rreduced ed ducced d aatherosclerotic therrosscl ther cler erootic oti lesion esion forma formation atiion iin n th tthee ao aaortas rtas rt as and nd aaortic o tiic ro or root roots otss of ot o bboth othh hy ot hyperlipidemic ype perl rlip rl ipid ip idem id emic em i sstrains. ic trai tr ains ai n . Th ns Thee 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, and ADAMTS7 is expressed at all stages in human plaques. Therefore further analysis is clearly required in order to understand the significance of these observations. Consistent with the association of ADAMTS7 with atherosclerosis but not with myocardial
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infarction, Bauer et al5 detected a tendency of plaques in Adamts7-null mice to develop a larger fibrous cap, a finding that should be fully explored to determine whether targeting ADAMTS7 in patients might result not only in decreased atherosclerosis but also in more stable plaques. Studies are also needed to investigate whether atherosclerosis-associated ADAMTS7 genetic variants associate with restenosis or arterial calcification, as recently suggested.6 Overall, the studies presented by Bauer at al5 provide the first firm evidence that mouse Adamts7 plays a proatherogenic role, likely through the promotion of VSMC migration. The long-term success of percutaneous coronary intervention is limited by restenosis, a pathological process characterized by excessive neointimal thickening caused by the nflammatory response associated with mechanical injury to the vessel wall.7 Lik Like ik ke na nnative tive tive inflammatory atherosclerosis, restenosis involves activation of zinc metalloproteinases that alter the ECM.2 Th he st stud udie ud iess by ie b B aueer and colleagues5 and Kessl au Kessler ler aand nd colleaguess8 (a se second econd co study also published The studies Bauer inn this thhis hi issue off Circulation) Circul ullatio ionn) both both report rep epor orrt that that genetic geenetticc deletion deeleeti tion onn ooff Adamts7 Adam Ad amts tss7 reduces reedu duce cess ne nneointimal oinntim oi mall thickening wire These consistent with hic icke keni ke n ngg after ni aft fter er w ire inju ire iinjury nju ury to to the the femoral femo fe mo ora rall and andd carotid an c rot ca rotidd arteries. arrte terries riess. Thes T hes esee rresults essult ltss ar aree co con nsis issteent w itth previous studi studies diies sshowing howi ho wing wi n tthat ng hatt Ad ha Adam Adamts7 amts am t 7 in increases ncr crea ease ea sess nneointima se eoin eo inti tima ti ma fformation orma or m ti tion on iin n ba ball balloon-injured lloo oonoo n in nnju jured rat arteries by stimulating VSMC migration through the degradation of cartilage oligomeric matrix protein (COMP, also called thrombospondin-5).9 Kessler and colleagues8 shed further light on the role of Adamts7 in vascular remodeling by focusing on vessel re-endothelialization, which is inversely related to neointima formation. They found that Adamts7 inhibits EC proliferation and migration in vitro and that reendothelialization is strongly augmented in the injured vessels in Adamts7-null mice.8 Surprisingly, COMP expression did not affect EC proliferation/migration in vitro, and Comp deficiency had no effect on reendothelialization in injured arteries, suggesting that Adamts7 retards endothelium repair via COMP-independent mechanisms.8 Using label-free
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LC MS/MS secretome analysis, coimmunoprecipitation strategies and mammalian two-hybrid analysis, Kessler and coworkers8 found that Adamts7 can bind directly to thrombospondin-1 (TSP-1) and degrade it in vitro. In agreement with earlier mouse studies showing the beneficial effects of TSP-1 inactivation on reendothelialization and neointima formation,10 the inhibitory effect of Adamts7 overexpression on EC proliferation and migration was blunted in Tsp-1 silenced endothelial cells in vitro, and Adamts7-dependent inhibition of reendothelialization was circumvented in Tsp-1-null mice.8 The study by Kessler et al8 thus suggests that ADAMTS7 exerts complementary functions in neointima formation by selective and cell-type-dependent substrate processing: COMP cleavage mediating augmented VSMC migration whereas TSP-1 reeleevaancce of degradation mediates impaired EC recovery (Figure 1). However, the in vivo relevance Adamts7-mediated processing in EC responses during neointima formation remains undefined. EC C-s -spe peci cifi ifi ficc Ad A am mts7 ts7 deletion in conditional mou ouse ou se models will help hel e p too confirm con o firm the EC-selective EC-specific Adamts7 mouse ffunction unccti t on of Ad dam mts77 aand ndd re rec concil con ncilee th tthee ddata ata aabout boutt it ts ex xpres presssiion an nd ffunction nd uncctio io on in E Cs iin n vi vivo vo o (s see Adamts7 reconcile its expression and ECs (see be elo low) w).. w) below). Both h Ad Adamts7-null A Adam dam amts ts77-n ts nul u l mo mous mouse usee st us strains tra r in ns ha have ve a La LacZ LacZ Z rreporter epor ep orte or terr ge te genee iin n th thee ge ggene-trapping ne-t ne -ttra rapp ppin pp i g cassette cassette, e allowing for X-gal staining as readout of active Adamts7 expression, which was detected in heart tissue and pulmonary vasculature.5, 8 This staining allowed analysis of the dynamics of Adamts7 expression in SM-D-actin-immunoreactive cells in response to mechanical vascular injury and hyperlipidemia, revealing an early, transient upregulation,5 consistent with the action of ADAMTS7 as a positive regulator of neointimal thickening. Notably, previous in vitro findings showed upregulation of ADAMTS7 expression in VSMCs by inflammatory cytokines (TNFĮ, IL-1, PDGFB), but not by anti-inflammatory cytokines (TGFB) or oxidized LDL.4 This would suggest that ADAMTS7 responds to inflammation rather than to hyperlipidemia, in line with the
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recognized role of ADAMTS7 in arthritis.4 The study by Bauer et al5 also provides insight into the cell distribution of Adamts7, which is mainly detected in the media and adventitia of mouse aortas but not in ECs. Further expression studies are needed to clarify the spatial and temporal pattern of ADAMTS7 expression in the cell types of the injured vessel wall—including direct immunohistochemical detection of Adamts7 in rodent arteries using specific antibodies and quantification of expression levels (e.g. real-time PCR, western blot). In contrast to the Adamts7 expression pattern in the media and adventitia of mouse arteries, immunohistochemistry analysis in human coronary and carotid arteries revealed ADAMTS7 expression in only a proportion of VSMCs in atherosclerotic plaques, predominantly near the media-intima border and the fibrous cap.5, 11 The absence of ADAMTS7 staining in CD68-labeled CD68-labeled macrophages indicates indiicaatees the the need need for further work to expand the repertoire of molecular markers for selective cell subsets, in order to better be ettter ddefine efin ef inee tthe in hee po pop populations pulations expressing ADAMT ADAMTS7 MTS MT S7 in the intimaa ooff hu human uman atherosclerotic plaques. pl laq que u s. It will ll be be also allsoo important imp mpor orrtaant to to analyze an nallyzee ADAMTS7 ADAM AMTS AM S7 expression ex xprres esssio sion in in human huumaan atherosclerotic athe at hero he ro osc scleeroti rotic ic and and restenotic est sten enot en o ic lesions ot les esio ionns at at different difffer eren entt stages sttag ages es of of disease dise di seaasee progression. se prog pr ogre og r ssio ionn. io n. The st tud udyy by B a err eett all5 ppositions au ositio os ions io ns A ADAMTS7 DAMT DA MTS7 MT S iin S7 n pr prim primary imar im aryy ao ar aort aortic rtic rt ic V VSMCs SMCs SM Cs iin n sp sspecialized ecialized study Bauer membrane protrusions called podosomes, which are actively involved in matrix degradation and cell invasiveness. In this location, ADAMTS7 might associate with adhesion receptors such as integrins or other proteases to exert coordinated functions in vascular remodeling.12 Given the emerging idea that podosomes can sense matrix stiffness,13 it is appealing to propose that ADAMTS7 modulates matrix tension in the vessel wall by processing COMP near podosomes to interfere with its binding to Į7ȕ1 integrin—a recognized mechanosensor at myotendinous junctions14—which could ultimately lead to pathologic vascular remodeling.15 ADAMTS7 posseses mucin-proteoglycan domains, and interacts with COMP through its
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four C-terminal TSP repeats.4 Additional structural studies of the ADAMTS7/COMP complex will shed light on the potential value of targeting the ADAMTS7 catalytic site or selective exosite binding motifs to avoid adverse effects on related proteases such as ADAMTS12, which is also able to process COMP.16 The identification by Kessler et al8 of the matricellular protein TSP-1 as a novel ADAMTS7 substrate in ECs is important, but the selectivity of this processing and its role in vascular remodeling is as yet unclear since TSP1 can be cleaved by other metalloproteases, including ADAMTS1, ADAMTS13 and MT1-MMP.17 It will also be important to identify the ADAMTS7 clevage sites in COMP and TSP-1 and define whether they are unique or shared with other metalloproteases, and whether cleavage can generate bioactive polypeptide fragments able to bind cell receptors that trigger EC and VSMC resp pon nse s s. s T he responses. The dentification of specific ADAMTS7 cleavage sites would also permit direct in vivo investigation identification off tthe he rrelevance elev el lev evan an ncee ooff CO C MP and TSP-1 processing ng g too atherosclerosi siis by y ggenerating en enerating cleavageCOMP atherosclerosis esiist stant knock-in knocckk-in i m in ice, ic e, aass pr pre evious evio usly us ly ac chieeveed fo or col llagen lla agen n I pprocessing. roccess cessin ingg.18 Si in Since S inc ncee AD ADAMTS7 ADAM AMTS AM T 7 is TS resistant mice, previously achieved for collagen thought hou ough ghtt to bbee a nnonredundant gh onnred nred dunnda dant nt m member embe em b r off tthe be he A ADAMTS DAMT DA MTS MT S fa fam family, mily mily ly,,4 the he search searrch for f r other fo othe ot herr unique he unniq que ADAMTS7 substrates suubs b trrat ates ess and andd interacting int nterrac acttin ng pr prot otei ot eins ei ns iin n th thee ar arte tery te ry w alll mi al igh ghtt al also so pprovide rovi ro vide vi de nnew ew proteins artery wall might opportunities for therapeutic intervention. The studies by Bauer and colleagues5 and Kessler and colleagues8 conclusively demonstrate a pro-atherogenic role for mouse Adamts7. A key outstanding question is whether any of these laboratory findings in mouse models can be translated back to the clinic (Figure 2). Recent studies have begun to assess whether human ADAMTS7 alleles associated with high risk of coronary atherosclerosis are linked to higher ADAMTS7 expression or activity in tissues and cells involved in disease development. For example, the rs3825807 G/G genotype in the ADAMTS7 locus, which is associated with lower atherosclerosis prevalence and severity, reduces
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not the expression of ADAMTS7 but its maturation and activity, resulting in reduced COMP cleavage and attenuated VSMC migration.11 It will be of interest to assess whether the rs3825807 G/G genotype also affects TSP-1 degradation in ECs. Further research in this area could lead to personalized medicine based on the identification of ADAMTS7 genetic variants in patients with atherosclerosis who could benefit from strategies targeting this proteolytic pathway. Quantification of COMP or TSP-1 fragments in plasma of these patients might also provide valuable information about the severity or progression of atherosclerotic disease, as shown for COMP in arthritis.19 Despite the lack of success with inhibitors of the closely related MMP subfamily, the strong GWAS association of ADAMTS7 with atherosclerosis, together with the solid olid knowledge being generated about the mechanisms of action of ADAMTS7ADAMTS7-mediated 7--meediiat ated ed vascular remodeling, may pave the way for the development of novel strategies to ameliorate atherosclerosis attheero rosscle scle lero rosi ro s s and si an nd restenosis. restenosis. These therapeuticc approaches ap pproaches might mig ght h include inc nclu ludde targeting ADAMTS7 lu catalytic caataaly l tic or C-t C-terminal -ter errmina nall exos eexosites, xos osit itees,, lo it locking ock ckin ng the A ADAMTS7 DAM AMTS AM S7 pr prop propetide-catalytic oppet etiide-ca cata taaly yti ticc do ddomain oma maain n conformation co onf n or orma m tiion (as ma (ass in in the th he G/G G G rs3825807 G/ rs38 3825 2580 25 8077 variant), vari va rian ri nt) t),, delivering dellivveri de veri ring ng substrates sub ubsstraates ub e to to restore rest re stor st orre homeostasis hom ho meost meo ostasi tasiss (e.g. e.g. via vira viral-based all-ba base ba seed ap appr approaches), p oaach pr ches ess), ) inhibiting inh nhib bit itiing signaling sig igna nali na liing pathways pat athw hway hw ayss tr ay ttriggered ig gge gere redd by A re ADAMTS7 DAMT DA MTS7 MT substrate fragments, or decreasing ADAMTS7 expression by miR29-mimics.20
Acknowledgments: The authors thank Simon Bartlett for editorial assistance. We apologize to colleagues whose work has been cited indirectly through review articles.
Funding Sources: Work in VA´s laboratory is supported by grants SAF2013-46663-R and RD12/0042/0028 from the Spanish Ministry of Economy and Competitiveness (MINECO) with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER), the European Commission (Liphos, Grant Agreement No 317916), and the Progeria Research Foundation (Established Investigator Award). Work in AGA’s laboratory is supported by grants SAF201125619 and RD12/0042/0023 from MINECO (FEDER co-funded), the European Commission
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(CardioNext, Grant Agreement No 608027), and La Marató de TV3 Foundation. CNIC is supported by the MINECO and the Pro-CNIC Foundation.
Conflict of Interest Disclosures: None.
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and reduces neointima formation in balloon-injured rat carotid artery. Circulation. 1999;100:849-854. 11. Pu X, Xiao Q, Kiechl S, Chan K, Ng FL, Gor S, Poston RN, Fang C, Patel A, Senver EC, Shaw-Hawkins S, Willeit J, Liu C, Zhu J, Tucker AT, Xu Q, Caulfield MJ, Ye S. Adamts7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-diseaseassociated variant. Am J Hum Genet. 2013;92:366-374. 12. Lener T, Burgstaller G, Crimaldi L, Lach S, Gimona M. Matrix-degrading podosomes in smooth muscle cells. Eur J Cell Biol. 2006;85:183-189. 13. Schachtner H, Calaminus SD, Thomas SG, Machesky LM. Podosomes in adhesion, migration, mechanosensing and matrix remodeling. Cytoskeleton. 2013;70:572-589. 14. Lueders TN, Zou K, Huntsman HD, Meador B, Mahmassani Z, Abel M, Valero MC, Huey KA, Boppart MD. The alpha7beta1-integrin accelerates fiber hypertrophy and myogenesis following a single bout of eccentric exercise. Am J Physiol-Cell Ph. 2011;301:C938-946. 15. Welser JV, Lange N, Singer CA, Elorza M, Scowen P, Keef KD, Gerthofferr WT WT, Bu Burk rkin rk in D J. Burkin DJ. Loss of the alpha7 integrin promotes extracellular signal-regulated kinase activation activat atio io on and an nd altered alte al tere ered ed vascular remodeling. Circ Res. 2007;101:672-681. 16 6. Liu Liu CJ, CJ, Kong K ngg W, Ko W, Xu K, Luan Y, Ilalov K, Sehgal Seehg hgal B, Yu S, Howell Hoowell lll RD, RD, D Di Cesare PE. 16. Ada Ad amts-122 as amt asso ociiat a es w itth an andd de degr g ad gr ades es ccartilage arti ar tila lage gee ooligomeric ligo gome merric me i m atrix atr rix pr pprotein. o ein. ot n J Bi Biol ol C heem. Adamts-12 associates with degrades matrix Chem. 2006;281:158 06 800 0-1 -158 8 0 8. 2006;281:15800-15808. 177. Koziol Kozi Ko ziol ol A onzal nzaloo P, P, M o a A, ot A, P olla ol l n A, la A, L oreenzzo C, Colome Colom omee N, om N Montaner Monnta tanner ner D, Dopazo Doppaz azoo J,, 17. A,, Go Gonzalo Mota Pollan Lorenzo Arri riba bas JJ,, C an nal als F, A rroy yo AG AG. Th The prot otea ease se m t -m t1 mmp ddrives rive ri ves a co comb mbinat ator o ia iall pr pproteolytic otteo eoly yti ticc Arribas Canals Arroyo protease mt1-mmp combinatorial act ctiv iv vatted eendothelial n otthe nd heli l al cells. cellls l . FA FASE SEB SE B J. J 20 2012 1 ;2 12 26: 6:44 4481 44 81 1-4 449 94. program in activated FASEB 2012;26:4481-4494. 18. Fukumoto Y, Deguchi JO, Libby P, Rabkin-Aikawa E, Sakata Y, Chin MT, Hill CC, Lawler PR, Varo N, Schoen FJ, Krane SM, Aikawa M. Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques. Circulation. 2004;110:1953-1959. 19. Hoch JM, Mattacola CG, Medina McKeon JM, Howard JS, Lattermann C. Serum cartilage oligomeric matrix protein (scomp) is elevated in patients with knee osteoarthritis: A systematic review and meta-analysis. Osteoarthr Cartilage. 2011;19:1396-1404. 20. Du Y, Gao C, Liu Z, Wang L, Liu B, He F, Zhang T, Wang Y, Wang X, Xu M, Luo GZ, Zhu Y, Xu Q, Wang X, Kong W. Upregulation of a disintegrin and metalloproteinase with thrombospondin motifs-7 by mir-29 repression mediates vascular smooth muscle calcification. Arterioscler Thromb Vasc Biol. 2012;32:2580-2588.
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Figure Legends:
Figure 1. ADAMTS7-mediated actions on vascular smooth muscle cells and endothelial cells promote neointima formation. ADAMTS7 expression is upregulated in vascular smooth muscle cells (VSMCs) upon vascular injury, leading to processing of the Į7ȕ1 integrin ligand COMP (cartilage oligomeric matrix protein) and increased VSMC migration. Complementary actions of ADAMTS7 have been proposed in endothelial cells (ECs) via cleavage of thrombospondin-1 (TSP-1), resulting in bioactive TSP-1 fragments that would reduce EC migration and proliferation and thus impair EC recovery. However, more evidence is needed about ADAMTS7 expression and actions on ECs in vivo. The combined effect of Adamts7-mediate teed in iincreased crea ease sedd se Adamts7-mediated VSMC migration and impaired re-endothelialization ultimately leads to increased neointima fo orm mat atio ion. io n n. formation.
Figu Fi gure gu re 22.. Pr Pro opossed opos d ttranslation rannsla ra latiion on ooff re rese seaarch arch oon n AD ADAM AMTS TS77 in TS in aatherosclerosis t er th e os oscl cleeroosis osiss and an nd cardiovascular carrdio ca rd ovaasc scuulaar ar Figure Proposed research ADAMTS7 disease from m bedside bed edsi side si de to to bench benc be nchh and nc and back b ck ba k again. aga gaiin. n Clinical Cli l ni nica c l and ca and basic basi ba sicc research si reese sear arch ar ch oon n AD ADAM AMTS AM T 7 in ADAMTS7 cardiovascular disease (CVD) exemplifies successful translational research. The identification of ADAMTS7 variants associated with atherosclerosis (AT) by GWAS in patients prompted basic researchers to generate loss-of-function mouse models to directly test the pathogenic role of ADAMTS7 in atherosclerosis. Two independent studies in this issue of Circulation show that Adamts7 deletion protects mice from atherosclerosis and restenosis.5, 8 Potential applications of Adamts7-related laboratory findings in the clinic include genetic analysis of CVD risk, use of ADAMTS7 substrates as biomarkers for AT progression, and personalized medicine in selected patients with pathogenic ADAMTS7 variants.
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VSMC
ADAMTS7
Į7ȕ1
Į7ȕ1
COMP
COMP fragments
Vascular injury (hyperlipidemia, angioplasty)
VSMC migration Impaired EC recovery
EC C
hy’ ‘Healthy’ wa all vessel wall
Neo ointi Neointimal le esion fo orm lesion formation
AD DAMTS MTS7 ADAMTS7
? TSP-1 adventitia media
Bioactive TSP-1 fragments
endothelium neointima
Figure 1
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Bedside dside GWAS identification entification TS7 vvariants arian nts of ADAMTS7 ia ated to to associated scle erosis atherosclerosis enosis? (restenosis? cation?) calcification?)
Figure 2
Bedside Bedside Bench Adamts7 deletion m protects from atheroscle erosis a nd atherosclerosis and vvascular ascular restenosis resten nosiss in in mou use models mo ode els mouse
Potential future fu uture applications: applicat •Genetic ADAMTS7-based diag gnosis of CVD/AT risk diagnosis •ADAMTS S7 ssubstrates ubstrates a s •ADAMTS7 as bio omarkers of of AT AT pr rogre ess biomarkers progression •T Therrapies targeting targ geting gA DAM •Therapies ADAMTS7 (personalized medicine?) medicine?) (personalized
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ADAMTS7 in Cardiovascular Disease: From Bedside to Bench and Back Again? Alicia G. Arroyo and Vicente Andrés Circulation. published online February 20, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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ADAMTS7 in Cardiovascular Disease: From Bedside to Bench and Back Again?
Running title: Arroyo et al.; Role of ADAMTS7 in vascular remodeling
Alicia G. Arroyo, MD, PhD1; Vicente Andrés, PhD2
1
Laboratory of Matrix Metalloproteinases in Angiogenesis and Inflammation; 2La Laboratory L boratory off
Mole Mo leecu c laar an andd Ge G netic Cardiovascular Pathoph phys ph y iology, Vascular B iology Program, Centro io Molecular Genetic Pathophysiology, Biology Nacional Naaciion onal al de de Investigaciones Inve In vest ve stig st ig gac acio ione io ness Cardiovasculares ne Card Ca rdio iova io v sc va s ulaaress C Carlos arlo ar loss II lo IIII (C (CNI (CNIC), NIC) NI C , Ma C) Madr Madrid, drid dr id,, Sp id Spain pai ainn
Address Ad ddr dres esss for for Correspondence: Corrres Co espo p nd nde dence ce:: Vicente Andrés, Andr drés dr és,, Ph és PhD D CNIC Melchor Fernández Almagro 3 28029 Madrid (Spain) Tel: +34-91 453 12 00 (Ext. 1502) Fax: +34-91 453 12 65 E-mail: [email protected]
Journal Subject Codes: Atherosclerosis:[89] Genetics of cardiovascular disease, Atherosclerosis:[145] Genetically altered mice, Atherosclerosis:[141] Functional genomics, Vascular biology:[96] Mechanism of atherosclerosis/growth factors Key words: ADAMTS7, COMP1, TSP-1, Editorial, matrix metalloproteinases, atherosclerosis, endothelialization, smooth muscle
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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, 4However, a causal link between this secreted zinc metalloprotease and atherosclerosis has yet to be established. In this issue of Circulation, Bauer and colleagues5 directly address this hypothesis by gene ge nera ne raati ting ngg whole-body whole lee-b -bod o y knock-out mice for Adam mts ts77 for the investigation invessti t gati tiion of atherosclerosis generating Adamts7 ddevelopment. dev evelopment. ve T The he aut authors utho hoors ccrossed rossed ros ssed d Adam Adamts7-null A dam amts7--nu -null mice mi with wit ithh the th he atherosusceptible athhero rossuscep pti tibble ble ap aapoE-KO oE--KO and oE and nd Ld Ldlr-KO dlr lr-K -KO -K O mo mou mouse use mo use mode models deels aand nd ffound ou und tthat hatt de ha dele deletion lettion le on ooff Ad Adam Adamts7 amts am ts77 ssignificantly ts ignnifi ig nifiica cant nttly y rreduced ed ducced d aatherosclerotic therrosscl ther cler erootic oti lesion esion forma formation atiion iin n th tthee ao aaortas rtas rt as and nd aaortic o tiic ro or root roots otss of ot o bboth othh hy ot hyperlipidemic ype perl rlip rl ipid ip idem id emic em i sstrains. ic trai tr ains ai n . Th ns Thee 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, and ADAMTS7 is expressed at all stages in human plaques. Therefore further analysis is clearly required in order to understand the significance of these observations. Consistent with the association of ADAMTS7 with atherosclerosis but not with myocardial
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infarction, Bauer et al5 detected a tendency of plaques in Adamts7-null mice to develop a larger fibrous cap, a finding that should be fully explored to determine whether targeting ADAMTS7 in patients might result not only in decreased atherosclerosis but also in more stable plaques. Studies are also needed to investigate whether atherosclerosis-associated ADAMTS7 genetic variants associate with restenosis or arterial calcification, as recently suggested.6 Overall, the studies presented by Bauer at al5 provide the first firm evidence that mouse Adamts7 plays a proatherogenic role, likely through the promotion of VSMC migration. The long-term success of percutaneous coronary intervention is limited by restenosis, a pathological process characterized by excessive neointimal thickening caused by the nflammatory response associated with mechanical injury to the vessel wall.7 Lik Like ik ke na nnative tive tive inflammatory atherosclerosis, restenosis involves activation of zinc metalloproteinases that alter the ECM.2 Th he st stud udie ud iess by ie b B aueer and colleagues5 and Kessl au Kessler ler aand nd colleaguess8 (a se second econd co study also published The studies Bauer inn this thhis hi issue off Circulation) Circul ullatio ionn) both both report rep epor orrt that that genetic geenetticc deletion deeleeti tion onn ooff Adamts7 Adam Ad amts tss7 reduces reedu duce cess ne nneointimal oinntim oi mall thickening wire These consistent with hic icke keni ke n ngg after ni aft fter er w ire inju ire iinjury nju ury to to the the femoral femo fe mo ora rall and andd carotid an c rot ca rotidd arteries. arrte terries riess. Thes T hes esee rresults essult ltss ar aree co con nsis issteent w itth previous studi studies diies sshowing howi ho wing wi n tthat ng hatt Ad ha Adam Adamts7 amts am t 7 in increases ncr crea ease ea sess nneointima se eoin eo inti tima ti ma fformation orma or m ti tion on iin n ba ball balloon-injured lloo oonoo n in nnju jured rat arteries by stimulating VSMC migration through the degradation of cartilage oligomeric matrix protein (COMP, also called thrombospondin-5).9 Kessler and colleagues8 shed further light on the role of Adamts7 in vascular remodeling by focusing on vessel re-endothelialization, which is inversely related to neointima formation. They found that Adamts7 inhibits EC proliferation and migration in vitro and that reendothelialization is strongly augmented in the injured vessels in Adamts7-null mice.8 Surprisingly, COMP expression did not affect EC proliferation/migration in vitro, and Comp deficiency had no effect on reendothelialization in injured arteries, suggesting that Adamts7 retards endothelium repair via COMP-independent mechanisms.8 Using label-free
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LC MS/MS secretome analysis, coimmunoprecipitation strategies and mammalian two-hybrid analysis, Kessler and coworkers8 found that Adamts7 can bind directly to thrombospondin-1 (TSP-1) and degrade it in vitro. In agreement with earlier mouse studies showing the beneficial effects of TSP-1 inactivation on reendothelialization and neointima formation,10 the inhibitory effect of Adamts7 overexpression on EC proliferation and migration was blunted in Tsp-1 silenced endothelial cells in vitro, and Adamts7-dependent inhibition of reendothelialization was circumvented in Tsp-1-null mice.8 The study by Kessler et al8 thus suggests that ADAMTS7 exerts complementary functions in neointima formation by selective and cell-type-dependent substrate processing: COMP cleavage mediating augmented VSMC migration whereas TSP-1 reeleevaancce of degradation mediates impaired EC recovery (Figure 1). However, the in vivo relevance Adamts7-mediated processing in EC responses during neointima formation remains undefined. EC C-s -spe peci cifi ifi ficc Ad A am mts7 ts7 deletion in conditional mou ouse ou se models will help hel e p too confirm con o firm the EC-selective EC-specific Adamts7 mouse ffunction unccti t on of Ad dam mts77 aand ndd re rec concil con ncilee th tthee ddata ata aabout boutt it ts ex xpres presssiion an nd ffunction nd uncctio io on in E Cs iin n vi vivo vo o (s see Adamts7 reconcile its expression and ECs (see be elo low) w).. w) below). Both h Ad Adamts7-null A Adam dam amts ts77-n ts nul u l mo mous mouse usee st us strains tra r in ns ha have ve a La LacZ LacZ Z rreporter epor ep orte or terr ge te genee iin n th thee ge ggene-trapping ne-t ne -ttra rapp ppin pp i g cassette cassette, e allowing for X-gal staining as readout of active Adamts7 expression, which was detected in heart tissue and pulmonary vasculature.5, 8 This staining allowed analysis of the dynamics of Adamts7 expression in SM-D-actin-immunoreactive cells in response to mechanical vascular injury and hyperlipidemia, revealing an early, transient upregulation,5 consistent with the action of ADAMTS7 as a positive regulator of neointimal thickening. Notably, previous in vitro findings showed upregulation of ADAMTS7 expression in VSMCs by inflammatory cytokines (TNFĮ, IL-1, PDGFB), but not by anti-inflammatory cytokines (TGFB) or oxidized LDL.4 This would suggest that ADAMTS7 responds to inflammation rather than to hyperlipidemia, in line with the
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recognized role of ADAMTS7 in arthritis.4 The study by Bauer et al5 also provides insight into the cell distribution of Adamts7, which is mainly detected in the media and adventitia of mouse aortas but not in ECs. Further expression studies are needed to clarify the spatial and temporal pattern of ADAMTS7 expression in the cell types of the injured vessel wall—including direct immunohistochemical detection of Adamts7 in rodent arteries using specific antibodies and quantification of expression levels (e.g. real-time PCR, western blot). In contrast to the Adamts7 expression pattern in the media and adventitia of mouse arteries, immunohistochemistry analysis in human coronary and carotid arteries revealed ADAMTS7 expression in only a proportion of VSMCs in atherosclerotic plaques, predominantly near the media-intima border and the fibrous cap.5, 11 The absence of ADAMTS7 staining in CD68-labeled CD68-labeled macrophages indicates indiicaatees the the need need for further work to expand the repertoire of molecular markers for selective cell subsets, in order to better be ettter ddefine efin ef inee tthe in hee po pop populations pulations expressing ADAMT ADAMTS7 MTS MT S7 in the intimaa ooff hu human uman atherosclerotic plaques. pl laq que u s. It will ll be be also allsoo important imp mpor orrtaant to to analyze an nallyzee ADAMTS7 ADAM AMTS AM S7 expression ex xprres esssio sion in in human huumaan atherosclerotic athe at hero he ro osc scleeroti rotic ic and and restenotic est sten enot en o ic lesions ot les esio ionns at at different difffer eren entt stages sttag ages es of of disease dise di seaasee progression. se prog pr ogre og r ssio ionn. io n. The st tud udyy by B a err eett all5 ppositions au ositio os ions io ns A ADAMTS7 DAMT DA MTS7 MT S iin S7 n pr prim primary imar im aryy ao ar aort aortic rtic rt ic V VSMCs SMCs SM Cs iin n sp sspecialized ecialized study Bauer membrane protrusions called podosomes, which are actively involved in matrix degradation and cell invasiveness. In this location, ADAMTS7 might associate with adhesion receptors such as integrins or other proteases to exert coordinated functions in vascular remodeling.12 Given the emerging idea that podosomes can sense matrix stiffness,13 it is appealing to propose that ADAMTS7 modulates matrix tension in the vessel wall by processing COMP near podosomes to interfere with its binding to Į7ȕ1 integrin—a recognized mechanosensor at myotendinous junctions14—which could ultimately lead to pathologic vascular remodeling.15 ADAMTS7 posseses mucin-proteoglycan domains, and interacts with COMP through its
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four C-terminal TSP repeats.4 Additional structural studies of the ADAMTS7/COMP complex will shed light on the potential value of targeting the ADAMTS7 catalytic site or selective exosite binding motifs to avoid adverse effects on related proteases such as ADAMTS12, which is also able to process COMP.16 The identification by Kessler et al8 of the matricellular protein TSP-1 as a novel ADAMTS7 substrate in ECs is important, but the selectivity of this processing and its role in vascular remodeling is as yet unclear since TSP1 can be cleaved by other metalloproteases, including ADAMTS1, ADAMTS13 and MT1-MMP.17 It will also be important to identify the ADAMTS7 clevage sites in COMP and TSP-1 and define whether they are unique or shared with other metalloproteases, and whether cleavage can generate bioactive polypeptide fragments able to bind cell receptors that trigger EC and VSMC resp pon nse s s. s T he responses. The dentification of specific ADAMTS7 cleavage sites would also permit direct in vivo investigation identification off tthe he rrelevance elev el lev evan an ncee ooff CO C MP and TSP-1 processing ng g too atherosclerosi siis by y ggenerating en enerating cleavageCOMP atherosclerosis esiist stant knock-in knocckk-in i m in ice, ic e, aass pr pre evious evio usly us ly ac chieeveed fo or col llagen lla agen n I pprocessing. roccess cessin ingg.18 Si in Since S inc ncee AD ADAMTS7 ADAM AMTS AM T 7 is TS resistant mice, previously achieved for collagen thought hou ough ghtt to bbee a nnonredundant gh onnred nred dunnda dant nt m member embe em b r off tthe be he A ADAMTS DAMT DA MTS MT S fa fam family, mily mily ly,,4 the he search searrch for f r other fo othe ot herr unique he unniq que ADAMTS7 substrates suubs b trrat ates ess and andd interacting int nterrac acttin ng pr prot otei ot eins ei ns iin n th thee ar arte tery te ry w alll mi al igh ghtt al also so pprovide rovi ro vide vi de nnew ew proteins artery wall might opportunities for therapeutic intervention. The studies by Bauer and colleagues5 and Kessler and colleagues8 conclusively demonstrate a pro-atherogenic role for mouse Adamts7. A key outstanding question is whether any of these laboratory findings in mouse models can be translated back to the clinic (Figure 2). Recent studies have begun to assess whether human ADAMTS7 alleles associated with high risk of coronary atherosclerosis are linked to higher ADAMTS7 expression or activity in tissues and cells involved in disease development. For example, the rs3825807 G/G genotype in the ADAMTS7 locus, which is associated with lower atherosclerosis prevalence and severity, reduces
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not the expression of ADAMTS7 but its maturation and activity, resulting in reduced COMP cleavage and attenuated VSMC migration.11 It will be of interest to assess whether the rs3825807 G/G genotype also affects TSP-1 degradation in ECs. Further research in this area could lead to personalized medicine based on the identification of ADAMTS7 genetic variants in patients with atherosclerosis who could benefit from strategies targeting this proteolytic pathway. Quantification of COMP or TSP-1 fragments in plasma of these patients might also provide valuable information about the severity or progression of atherosclerotic disease, as shown for COMP in arthritis.19 Despite the lack of success with inhibitors of the closely related MMP subfamily, the strong GWAS association of ADAMTS7 with atherosclerosis, together with the solid olid knowledge being generated about the mechanisms of action of ADAMTS7ADAMTS7-mediated 7--meediiat ated ed vascular remodeling, may pave the way for the development of novel strategies to ameliorate atherosclerosis attheero rosscle scle lero rosi ro s s and si an nd restenosis. restenosis. These therapeuticc approaches ap pproaches might mig ght h include inc nclu ludde targeting ADAMTS7 lu catalytic caataaly l tic or C-t C-terminal -ter errmina nall exos eexosites, xos osit itees,, lo it locking ock ckin ng the A ADAMTS7 DAM AMTS AM S7 pr prop propetide-catalytic oppet etiide-ca cata taaly yti ticc do ddomain oma maain n conformation co onf n or orma m tiion (as ma (ass in in the th he G/G G G rs3825807 G/ rs38 3825 2580 25 8077 variant), vari va rian ri nt) t),, delivering dellivveri de veri ring ng substrates sub ubsstraates ub e to to restore rest re stor st orre homeostasis hom ho meost meo ostasi tasiss (e.g. e.g. via vira viral-based all-ba base ba seed ap appr approaches), p oaach pr ches ess), ) inhibiting inh nhib bit itiing signaling sig igna nali na liing pathways pat athw hway hw ayss tr ay ttriggered ig gge gere redd by A re ADAMTS7 DAMT DA MTS7 MT substrate fragments, or decreasing ADAMTS7 expression by miR29-mimics.20
Acknowledgments: The authors thank Simon Bartlett for editorial assistance. We apologize to colleagues whose work has been cited indirectly through review articles.
Funding Sources: Work in VA´s laboratory is supported by grants SAF2013-46663-R and RD12/0042/0028 from the Spanish Ministry of Economy and Competitiveness (MINECO) with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER), the European Commission (Liphos, Grant Agreement No 317916), and the Progeria Research Foundation (Established Investigator Award). Work in AGA’s laboratory is supported by grants SAF201125619 and RD12/0042/0023 from MINECO (FEDER co-funded), the European Commission
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(CardioNext, Grant Agreement No 608027), and La Marató de TV3 Foundation. CNIC is supported by the MINECO and the Pro-CNIC Foundation.
Conflict of Interest Disclosures: None.
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and reduces neointima formation in balloon-injured rat carotid artery. Circulation. 1999;100:849-854. 11. Pu X, Xiao Q, Kiechl S, Chan K, Ng FL, Gor S, Poston RN, Fang C, Patel A, Senver EC, Shaw-Hawkins S, Willeit J, Liu C, Zhu J, Tucker AT, Xu Q, Caulfield MJ, Ye S. Adamts7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-diseaseassociated variant. Am J Hum Genet. 2013;92:366-374. 12. Lener T, Burgstaller G, Crimaldi L, Lach S, Gimona M. Matrix-degrading podosomes in smooth muscle cells. Eur J Cell Biol. 2006;85:183-189. 13. Schachtner H, Calaminus SD, Thomas SG, Machesky LM. Podosomes in adhesion, migration, mechanosensing and matrix remodeling. Cytoskeleton. 2013;70:572-589. 14. Lueders TN, Zou K, Huntsman HD, Meador B, Mahmassani Z, Abel M, Valero MC, Huey KA, Boppart MD. The alpha7beta1-integrin accelerates fiber hypertrophy and myogenesis following a single bout of eccentric exercise. Am J Physiol-Cell Ph. 2011;301:C938-946. 15. Welser JV, Lange N, Singer CA, Elorza M, Scowen P, Keef KD, Gerthofferr WT WT, Bu Burk rkin rk in D J. Burkin DJ. Loss of the alpha7 integrin promotes extracellular signal-regulated kinase activation activat atio io on and an nd altered alte al tere ered ed vascular remodeling. Circ Res. 2007;101:672-681. 16 6. Liu Liu CJ, CJ, Kong K ngg W, Ko W, Xu K, Luan Y, Ilalov K, Sehgal Seehg hgal B, Yu S, Howell Hoowell lll RD, RD, D Di Cesare PE. 16. Ada Ad amts-122 as amt asso ociiat a es w itth an andd de degr g ad gr ades es ccartilage arti ar tila lage gee ooligomeric ligo gome merric me i m atrix atr rix pr pprotein. o ein. ot n J Bi Biol ol C heem. Adamts-12 associates with degrades matrix Chem. 2006;281:158 06 800 0-1 -158 8 0 8. 2006;281:15800-15808. 177. Koziol Kozi Ko ziol ol A onzal nzaloo P, P, M o a A, ot A, P olla ol l n A, la A, L oreenzzo C, Colome Colom omee N, om N Montaner Monnta tanner ner D, Dopazo Doppaz azoo J,, 17. A,, Go Gonzalo Mota Pollan Lorenzo Arri riba bas JJ,, C an nal als F, A rroy yo AG AG. Th The prot otea ease se m t -m t1 mmp ddrives rive ri ves a co comb mbinat ator o ia iall pr pproteolytic otteo eoly yti ticc Arribas Canals Arroyo protease mt1-mmp combinatorial act ctiv iv vatted eendothelial n otthe nd heli l al cells. cellls l . FA FASE SEB SE B J. J 20 2012 1 ;2 12 26: 6:44 4481 44 81 1-4 449 94. program in activated FASEB 2012;26:4481-4494. 18. Fukumoto Y, Deguchi JO, Libby P, Rabkin-Aikawa E, Sakata Y, Chin MT, Hill CC, Lawler PR, Varo N, Schoen FJ, Krane SM, Aikawa M. Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques. Circulation. 2004;110:1953-1959. 19. Hoch JM, Mattacola CG, Medina McKeon JM, Howard JS, Lattermann C. Serum cartilage oligomeric matrix protein (scomp) is elevated in patients with knee osteoarthritis: A systematic review and meta-analysis. Osteoarthr Cartilage. 2011;19:1396-1404. 20. Du Y, Gao C, Liu Z, Wang L, Liu B, He F, Zhang T, Wang Y, Wang X, Xu M, Luo GZ, Zhu Y, Xu Q, Wang X, Kong W. Upregulation of a disintegrin and metalloproteinase with thrombospondin motifs-7 by mir-29 repression mediates vascular smooth muscle calcification. Arterioscler Thromb Vasc Biol. 2012;32:2580-2588.
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Figure Legends:
Figure 1. ADAMTS7-mediated actions on vascular smooth muscle cells and endothelial cells promote neointima formation. ADAMTS7 expression is upregulated in vascular smooth muscle cells (VSMCs) upon vascular injury, leading to processing of the Į7ȕ1 integrin ligand COMP (cartilage oligomeric matrix protein) and increased VSMC migration. Complementary actions of ADAMTS7 have been proposed in endothelial cells (ECs) via cleavage of thrombospondin-1 (TSP-1), resulting in bioactive TSP-1 fragments that would reduce EC migration and proliferation and thus impair EC recovery. However, more evidence is needed about ADAMTS7 expression and actions on ECs in vivo. The combined effect of Adamts7-mediate teed in iincreased crea ease sedd se Adamts7-mediated VSMC migration and impaired re-endothelialization ultimately leads to increased neointima fo orm mat atio ion. io n n. formation.
Figu Fi gure gu re 22.. Pr Pro opossed opos d ttranslation rannsla ra latiion on ooff re rese seaarch arch oon n AD ADAM AMTS TS77 in TS in aatherosclerosis t er th e os oscl cleeroosis osiss and an nd cardiovascular carrdio ca rd ovaasc scuulaar ar Figure Proposed research ADAMTS7 disease from m bedside bed edsi side si de to to bench benc be nchh and nc and back b ck ba k again. aga gaiin. n Clinical Cli l ni nica c l and ca and basic basi ba sicc research si reese sear arch ar ch oon n AD ADAM AMTS AM T 7 in ADAMTS7 cardiovascular disease (CVD) exemplifies successful translational research. The identification of ADAMTS7 variants associated with atherosclerosis (AT) by GWAS in patients prompted basic researchers to generate loss-of-function mouse models to directly test the pathogenic role of ADAMTS7 in atherosclerosis. Two independent studies in this issue of Circulation show that Adamts7 deletion protects mice from atherosclerosis and restenosis.5, 8 Potential applications of Adamts7-related laboratory findings in the clinic include genetic analysis of CVD risk, use of ADAMTS7 substrates as biomarkers for AT progression, and personalized medicine in selected patients with pathogenic ADAMTS7 variants.
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VSMC
ADAMTS7
Į7ȕ1
Į7ȕ1
COMP
COMP fragments
Vascular injury (hyperlipidemia, angioplasty)
VSMC migration Impaired EC recovery
EC C
hy’ ‘Healthy’ wa all vessel wall
Neo ointi Neointimal le esion fo orm lesion formation
AD DAMTS MTS7 ADAMTS7
? TSP-1 adventitia media
Bioactive TSP-1 fragments
endothelium neointima
Figure 1
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Bedside dside GWAS identification entification TS7 vvariants arian nts of ADAMTS7 ia ated to to associated scle erosis atherosclerosis enosis? (restenosis? cation?) calcification?)
Figure 2
Bedside Bedside Bench Adamts7 deletion m protects from atheroscle erosis a nd atherosclerosis and vvascular ascular restenosis resten nosiss in in mou use models mo ode els mouse
Potential future fu uture applications: applicat •Genetic ADAMTS7-based diag gnosis of CVD/AT risk diagnosis •ADAMTS S7 ssubstrates ubstrates a s •ADAMTS7 as bio omarkers of of AT AT pr rogre ess biomarkers progression •T Therrapies targeting targ geting gA DAM •Therapies ADAMTS7 (personalized medicine?) medicine?) (personalized
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ADAMTS7 in Cardiovascular Disease: From Bedside to Bench and Back Again? Alicia G. Arroyo and Vicente Andrés Circulation. published online February 20, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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