title: ADAM12: a genetic modifier of preclinical peripheral arterial disease.
abstract: In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia; The Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia; doa3q@virginia.edu.
authors.forename: Ayotunde O
authors.initials: AO
authors.lastname: Dokun
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Lingdan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Okutsu
authors.affiliation: Division of Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Surovi
authors.initials: S
authors.lastname: Hazarika
authors.affiliation: Division of Cardiology, Department of Medicine, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: W Schuyler
authors.initials: WS
authors.lastname: Jones
authors.affiliation: Division of Cardiology, Department of Medicine, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Damian
authors.initials: D
authors.lastname: Craig
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia; The Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: R John
authors.initials: RJ
authors.lastname: Lye
authors.affiliation: Division of Cardiology, Department of Medicine, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia; The Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072199:ADAM12 Protein; D000818:Animals; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058729:Peripheral Arterial Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D042787:Receptor, TIE-2 / Q000378:metabolism
chemical_list: D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C096115:Adam12 protein, mouse
keywords: angiogenesis; genetics and genes; ischemia; peripheral vascular disease