title: ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant.
abstract: Recent genome-wide association studies have revealed an association between variation at the ADAMTS7 locus and susceptibility to coronary artery disease (CAD). Furthermore, in a population-based study cohort, we observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a Ser-to-Pro substitution in the prodomain of the protease ADAMTS7. In light of these data, we sought a mechanistic explanation for this association. We found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) of the G/G genotype for rs3825807 had reduced migratory ability, and conditioned media of VSMCs of the G/G genotype contained less of the cleaved form of thrombospondin-5, an ADAMTS7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration. Furthermore, we found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by VSMCs of the G/G genotype and that the Ser-to-Pro substitution affected ADAMTS7 prodomain cleavage. The results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD rendering a reduction in ADAMTS7 function.
authors: William Harvey Research Institute, Queen Mary University of London, London, UK.
authors: Xiangyuan
authors: X
authors: Pu
authors: Qingzhong
authors: Q
authors: Xiao
authors: Stefan
authors: S
authors: Kiechl
authors: Kenneth
authors: K
authors: Chan
authors: Fu Liang
authors: FL
authors: Ng
authors: Shivani
authors: S
authors: Gor
authors: Robin N
authors: RN
authors: Poston
authors: Changcun
authors: C
authors: Fang
authors: Ashish
authors: A
authors: Patel
authors: Ece C
authors: EC
authors: Senver
authors: Sue
authors: S
authors: Shaw-Hawkins
authors: Johann
authors: J
authors: Willeit
authors: Chuanju
authors: C
authors: Liu
authors: Jianhua
authors: J
authors: Zhu
authors: Arthur T
authors: AT
authors: Tucker
authors: Qingbo
authors: Q
authors: Xu
authors: Mark J
authors: MJ
authors: Caulfield
authors: Shu
authors: S
authors: Ye
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071118:ADAMTS7 Protein; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D002465:Cell Movement / Q000235:genetics*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D064235:Matrilin Proteins; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human