ADAMTS7 in Cardiovascular Disease
2015; Lippincott Williams & Wilkins; Volume: 131; Issue: 13 Linguagem: Romeno
10.1161/circulationaha.115.015711
ISSN1524-4539
AutoresAlicia G. Arroyo, Vicente Andrés,
Tópico(s)Cell Adhesion Molecules Research
ResumoHomeCirculationVol. 131, No. 13ADAMTS7 in Cardiovascular Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBADAMTS7 in Cardiovascular DiseaseFrom Bedside to Bench and Back Again? Alicia G. Arroyo, MD, PhD and Vicente Andrés, PhD Alicia G. ArroyoAlicia G. Arroyo From Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. Search for more papers by this author and Vicente AndrésVicente Andrés From Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. Search for more papers by this author Originally published20 Feb 2015https://doi.org/10.1161/CIRCULATIONAHA.115.015711Circulation. 2015;131:1156–1159Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 31, 2015: Previous Version 1 Metzincins, a family of zinc metalloproteinases able to process all the extracellular matrix components, include the matrix metalloproteinase, 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 extracellular matrix, and these alterations instigate changes in the behavior of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs).2 Recent genome-wide association studies have identified ADAMTS7 as a novel locus associated with human coronary atherosclerosis.3,4 However, a causal link between this secreted zinc metalloproteinase and atherosclerosis has yet to be established.Articles see p 1191 and p 1202In this issue of Circulation, Bauer and colleagues5 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 knockout and Ldlr knockout 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 tumor necrosis factor-α. 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 to understand the significance of these observations. Consistent with the association of ADAMTS7 with atherosclerosis but not with myocardial 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 are associated 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 inflammatory response associated with mechanical injury to the vessel wall.7 Like native atherosclerosis, restenosis involves activation of zinc metalloproteinases that alter the extracellular matrix.2 The studies by Bauer and colleagues5 and Kessler and colleagues,8 a second study also published in this issue of Circulation, both report that genetic deletion of Adamts7 reduces neointimal thickening after wire injury to the femoral and carotid arteries. These results are consistent with previous studies showing that Adamts7 increases neointima formation in balloon-injured 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 re-endothelialization 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 re-endothelialization in injured arteries, suggesting that Adamts7 retards endothelium repair via COMP-independent mechanisms.8 Using label-free liquid chromatography mass spectrometry secretome analysis, coimmunoprecipitation strategies, and mammalian 2-hybrid analysis, Kessler and coworkers8 found that Adamts7 can bind directly to thrombospondin-1 and degrade it in vitro. In agreement with earlier mouse studies showing the beneficial effects of thrombospondin-1 inactivation on re-endothelialization and neointima formation,10 the inhibitory effect of Adamts7 overexpression on EC proliferation and migration was blunted in Tsp-1–silenced ECs in vitro, and Adamts7-dependent inhibition of re-endothelialization 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 mediates augmented VSMC migration, whereas thrombospondin-1 degradation mediates impaired EC recovery (Figure 1). However, the in vivo relevance of Adamts7-mediated processing in EC responses during neointima formation remains undefined. EC-specific Adamts7 deletion in conditional mouse models will help to confirm the EC-selective function of Adamts7 and reconcile the data about its expression and function in ECs in vivo (see below).Download figureDownload PowerPointFigure 1. ADAMTS7-mediated actions on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) promote neointima formation. ADAMTS7 expression is upregulated in VSMCs on vascular injury, leading to processing of the α7β1 integrin ligand cartilage oligomeric matrix protein (COMP) and increased VSMC migration. Complementary actions of ADAMTS7 have been proposed in 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 for ADAMTS7 expression and actions on ECs in vivo. The combined effect of Adamts7-mediated increased VSMC migration and impaired re-endothelialization ultimately leads to increased neointima formation.Both Adamts7-null mouse strains have a LacZ reporter gene in the gene-trapping cassette, allowing 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 smooth muscle-α-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 (tumor necrosis factor-α, interleukin-1, platelet-derived growth factor-B) but not by anti-inflammatory cytokines (transforming growth factor-β) or oxidized low-density lipoprotein.4 This would suggest that ADAMTS7 responds to inflammation rather than to hyperlipidemia, in line with the recognized role of ADAMTS7 in arthritis.4 The study by Bauer et al5 also provides insight into the cell distribution of Adamts7, which is detected mainly in the media and adventitia of mouse aortas but not in ECs. Further expression studies are needed to clarify the spatial and temporal patterns 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 (eg, real-time polymerase chain reaction, 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 macrophages indicates the need for further work to expand the repertoire of molecular markers for selective cell subsets to better define the populations expressing ADAMTS7 in the intima of human atherosclerotic plaques. It will be also important to analyze ADAMTS7 expression in human atherosclerotic and restenotic lesions at different stages of disease progression.The study by Bauer et al5 positions ADAMTS7 in primary aortic VSMCs in specialized 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 α7β1 integrin, a recognized mechanosensor at myotendinous junctions,14 which could ultimately lead to pathological vascular remodeling.15ADAMTS7 possesses mucin-proteoglycan domains and interacts with COMP through its 4 C-terminal thrombospondin 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 thrombospondin-1 as a novel ADAMTS7 substrate in ECs is important, but the selectivity of this processing and its role in vascular remodeling are as yet unclear because thrombospondin-1 can be cleaved by other metalloproteinases, including ADAMTS1, ADAMTS13, and MT1–matrix metalloproteinase.17 It will also be important to identify the ADAMTS7 cleavage sites in COMP and thrombospondin-1 and to define whether they are unique or shared with other metalloproteinase, as well as whether cleavage can generate bioactive polypeptide fragments able to bind cell receptors that trigger EC and VSMC responses. The identification of specific ADAMTS7 cleavage sites would also permit direct in vivo investigation of the relevance of COMP and thrombospondin-1 processing to atherosclerosis by generating cleavage-resistant knock-in mice, as previously achieved for collagen I processing.18 Because ADAMTS7 is thought to be a nonredundant member of the ADAMTS family,4 the search for other unique ADAMTS7 substrates and interacting proteins in the artery wall might also provide new opportunities for therapeutic intervention.The studies by Bauer and colleagues5 and Kessler and colleagues8 conclusively demonstrate a proatherogenic role for mouse Adamts7. A key unanswered 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 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 thrombospondin-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 thrombospondin-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 matrix metalloproteinase subfamily, the strong genome-wide association study association of ADAMTS7 with atherosclerosis, together with the solid knowledge being generated about the mechanisms of action of ADAMTS7-mediated vascular remodeling, may pave the way for the development of novel strategies to ameliorate atherosclerosis and restenosis. These therapeutic approaches might include targeting ADAMTS7 catalytic or C-terminal exosites, locking the ADAMTS7 propeptide-catalytic domain conformation (as in the G/G rs3825807 variant), delivering substrates to restore homeostasis (eg, via viral-based approaches), inhibiting signaling pathways triggered by ADAMTS7 substrate fragments, or decreasing ADAMTS7 expression by miR29 mimics.20Download figureDownload PowerPointFigure 2. Proposed translation of research on ADAMTS7 in atherosclerosis and cardiovascular disease (CVD) from bedside to bench and back again. Clinical and basic research on ADAMTS7 in CVD exemplifies successful translational research. The identification of ADAMTS7 variants associated with atherosclerosis (AT) by genome-wide association studies (GWASs) 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.AcknowledgmentsWe thank Simon Bartlett for editorial assistance. We apologize to colleagues whose work has been cited indirectly through review articles.Sources of FundingWork in Dr Andrés’ laboratory is supported by grants SAF2013-46663-R and RD12/0042/0028 from the Spanish Ministry of Economy and Competitiveness (MINECO) with cofunding 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 Dr Arroyo’s laboratory is supported by grants SAF2011-25619 and RD12/0042/0023 from MINECO (FEDER cofunded), the European Commission (CardioNext, grant agreement No. 608027), and La Marató de TV3 Foundation. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the MINECO and the Pro-CNIC Foundation.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Vicente Andrés, PhD, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain. E-mail [email protected]References1. Shiomi T, Lemaître V, D’Armiento J, Okada Y.Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases.Pathol Int. 2010; 60:477–496. doi: 10.1111/j.1440-1827.2010.02547.x.CrossrefMedlineGoogle Scholar2. 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Su C and Urban Z (2021) LTBP4 in Health and Disease, Genes, 10.3390/genes12060795, 12:6, (795) March 31, 2015Vol 131, Issue 13 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.115.015711PMID: 25712207 Originally publishedFebruary 20, 2015 KeywordsTSP-1matrix metalloproteinasesEditorialsADAMTS7endothelializationatherosclerosissmooth muscleCOMP1PDF download Advertisement SubjectsGenetically Altered and Transgenic ModelsGeneticsMechanismsOmics
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