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Am J Pathol. 2015 Apr;185(4):1145-55. doi: 10.1016/j.ajpath.2014.11.028. Epub 2015 Feb 7.

Myeloid A disintegrin and metalloproteinase domain 10 deficiency modulates atherosclerotic plaque composition by shifting the balance from inflammation toward fibrosis.

Author information

1
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.
2
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
3
Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
4
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
5
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.
6
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.
7
Department of Medical Biochemistry, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
8
Institute for Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
9
Institute for Biochemistry, Christian-Albrechts-University, Kiel, Germany.
10
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.

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.

PMID:
25659879
DOI:
10.1016/j.ajpath.2014.11.028
[Indexed for MEDLINE]

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