title: Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice.
abstract: BACKGROUND
  Genome-wide association studies have established ADAMTS7 as a locus for coronary artery disease in humans. However, these studies fail to provide directionality for the association between ADAMTS7 and coronary artery disease. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell migration, but a role for and the direction of impact of this gene in atherogenesis have not been shown in relevant model systems.
  
  
  RESULTS
  We bred an Adamts7 whole-body knockout mouse onto both the Ldlr and Apoe knockout hyperlipidemic mouse models. Adamts7(-/-)/Ldlr(-/-) and Adamts7(-/-)/Apoe(-/-) mice displayed significant reductions in lesion formation in aortas and aortic roots compared with controls. Adamts7 knockout mice also showed reduced neointimal formation after femoral wire injury. Adamts7 expression was induced in response to injury and hyperlipidemia but was absent at later time points, and primary Adamts7 knockout vascular smooth muscle cells showed reduced migration in the setting of tumor necrosis factor-α stimulation. ADAMTS7 localized to cells positive for smooth muscle cell markers in human coronary artery disease lesions, and subcellular localization studies in cultured vascular smooth muscle cells placed ADAMTS7 at the cytoplasm and cell membrane, where it colocalized with markers of podosomes.
  
  
  CONCLUSIONS
  These data represent the first in vivo experimental validation of the association of Adamts7 with atherogenesis, likely through modulation of vascular cell migration and matrix in atherosclerotic lesions. These results demonstrate that Adamts7 is proatherogenic, lending directionality to the original genetic association and supporting the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans, making it an attractive target for novel therapeutic interventions.
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|Division of Translational Medicine and Human Genetics, Philadelphia, PA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bauer
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|Division of Translational Medicine and Human Genetics, Philadelphia, PA.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Tohyama
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Jifu
authors.initials: J
authors.lastname: Yang
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Ou
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Institute of Translational Medicine and Therapeutics, Philadelphia, PA.
authors.forename: Georgios K
authors.initials: GK
authors.lastname: Paschos
authors.affiliation: The Children's Hospital of Philadelphia Department of Pathology and Laboratory Medicine, Philadelphia, PA.
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Parmacek
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|Division of Translational Medicine and Human Genetics, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.|The Institute of Translational Medicine and Therapeutics, Philadelphia, PA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.|The Cardiovascular Institute, Philadelphia, PA.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
mesh_terms: D051722:ADAM Proteins / Q000032:analysis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000071118:ADAMTS7 Protein; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D003327:Coronary Disease / Q000201:enzymology* / Q000473:pathology; D066273:Diet, Western / Q000009:adverse effects; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D058426:Neointima / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human; C496264:Adamts7 protein, mouse
keywords: atherosclerosis; coronary artery disease; genetics; genome-wide association study; metalloproteases; mice, knockout