title: Deficiency of MMP17/MT4-MMP proteolytic activity predisposes to aortic aneurysm in mice.
abstract: BACKGROUND
  Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome.
  
  
  OBJECTIVE
  To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology.
  
  
  RESULTS
  Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates.
  
  
  CONCLUSIONS
  Mmp17 proteolytic activity regulates vascular smooth muscle cell phenotype in the arterial vessel wall, and its absence predisposes to thoracic aortic aneurysm in mice. The rescue of part of the vessel-wall phenotype by a lentiviral strategy opens avenues for therapeutic intervention in these life-threatening disorders.
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Mara
authors.initials: M
authors.lastname: Martín-Alonso
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Ana B
authors.initials: AB
authors.lastname: García-Redondo
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Dongchuan
authors.initials: D
authors.lastname: Guo
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Emilio
authors.initials: E
authors.lastname: Camafeita
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Fernando
authors.initials: F
authors.lastname: Martínez
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Arántzazu
authors.initials: A
authors.lastname: Alfranca
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Nerea
authors.initials: N
authors.lastname: Méndez-Barbero
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Ángela
authors.initials: Á
authors.lastname: Pollán
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Camacho
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: David T
authors.initials: DT
authors.lastname: Denhardt
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
authors.forename: Dianna
authors.initials: D
authors.lastname: Milewicz
authors.affiliation: From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.). agarroyo@cnic.es.
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Arroyo
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000784:Aortic Dissection / Q000235:genetics*; D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000196:embryology / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D001019:Aortic Rupture / Q000209:etiology; D005109:Extracellular Matrix / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D020125:Mutation, Missense; D053495:Osteopontin / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D016326:Extracellular Matrix Proteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000804:Angiotensin II; C402225:MMP17 protein, human; D053504:Matrix Metalloproteinases, Membrane-Associated; C498537:Mmp17 protein, mouse
keywords: aneurysm; aorta; cardiovascular diseases; matrix metalloproteinase 17; matrix metalloproteinases; osteopontin