title: Myeloid A disintegrin and metalloproteinase domain 10 deficiency modulates atherosclerotic plaque composition by shifting the balance from inflammation toward fibrosis.
abstract: A disintegrin and metalloproteinase domain 10 (ADAM10) is a metalloprotease involved in cleavage of various cell surface molecules, such as adhesion molecules, chemokines, and growth factor receptors. Although we have previously shown an association of ADAM10 expression with atherosclerotic plaque progression, a causal role of ADAM10 in atherosclerosis has not been investigated. Bone marrow from conditional knockout mice lacking Adam10 in the myeloid lineage or from littermate controls was transplanted into lethally irradiated low density lipoprotein receptor Ldlr(-/-) mice on an atherogenic diet. Myeloid Adam10 deficiency did not affect plaque size, but it increased plaque collagen content. Matrix metalloproteinase 9 and 13 expression and matrix metalloproteinase 2 gelatinase activity were significantly impaired in Adam10-deficient macrophages, whereas their capacity to stimulate collagen production was unchanged. Furthermore, relative macrophage content in advanced atherosclerotic lesions was decreased. In vitro, Adam10-deficient macrophages showed reduced migration toward monocyte chemoattractant protein-1 and transmigration through collagen. In addition, Adam10-deficient macrophages displayed increased anti-inflammatory phenotype with elevated IL-10, and reduced production of proinflammatory tumor necrosis factor, IL-12, and nitric oxide in response to lipopolysaccharide. These data suggest a critical role of Adam10 for leukocyte recruitment, inflammatory mediator production, and extracellular matrix degradation. Thereby, myeloid ADAM10 may play a causal role in modulating atherosclerotic plaque stability.
authors: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Emiel P C
authors: EP
authors: van der Vorst
authors: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Mike
authors: M
authors: Jeurissen
authors: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Ine M J
authors: IM
authors: Wolfs
authors: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Anke
authors: A
authors: Keijbeck
authors: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Kosta
authors: K
authors: Theodorou
authors: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Erwin
authors: E
authors: Wijnands
authors: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Leon
authors: L
authors: Schurgers
authors: Institute for Biochemistry, Christian-Albrechts-University, Kiel, Germany; Heart Research Centre Göttingen, and the Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany; Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors: Silvio
authors: S
authors: Weber
authors: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Medical Biochemistry, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors: Marion J
authors: MJ
authors: Gijbels
authors: Department of Medical Biochemistry, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors: Anouk A J
authors: AA
authors: Hamers
authors: Institute for Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
authors: Daniela
authors: D
authors: Dreymueller
authors: Institute for Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors: Stefan
authors: S
authors: Rose-John
authors: Department of Medical Biochemistry, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors: Menno P J
authors: MP
authors: de Winther
authors: Institute for Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
authors: Andreas
authors: A
authors: Ludwig
authors: Institute for Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors: Paul
authors: P
authors: Saftig
authors: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors: Erik A L
authors: EA
authors: Biessen
authors: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands. Electronic address: marjo.donners@maastrichtuniversity.nl.
authors: Marjo M P C
authors: MM
authors: Donners
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency* / Q000378:metabolism*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005355:Fibrosis; D005434:Flow Cytometry; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011973:Receptors, LDL; D003094:Collagen; C045073:Cre recombinase; D019426:Integrases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse