• Thorsten Kessler, Lu Zhang, Ziyi Liu, Xiaoke Yin, Yaqian Huang, Yingbao Wang, Yi Fu, Manuel Mayr, Qing Ge, Qingbo Xu, Yi Zhu, Xian Wang, Kjestine Schmidt, Cor de Wit, Jeanette Erdmann, Heribert Schunkert, Zouhair Aherrahrou, and Wei Kong.
• From Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Germany (T.K., H.S.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China (L.Z., Z.L.,Y.H.,Y.W., Y.F., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China (L.Z., Z.L., Y.H., Y.W., Y.F., X.W., W.K.); Cardiovascular Division, Kings College London BHF Centre, United Kingdom (X.Y., M.M., Q.X.); Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China (Q.G.); School of Basic Medical Sciences, Tianjin University, Beijing, China (Y.Z.); Institut für Physiologie, Universität zu Lübeck, Germany (K.S., C.d.W.); Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V. (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (K.S., C.d.W., J.E., Z.A.); Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (J.E., Z.A.); and Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V. (German Center for Cardiovascular Research), partner site Munich Heart Alliance (MHA), München, Germany (H.S.).
• Circulation. 2015 Mar 31; 131 (13): 1191-201.

BackgroundADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, was recently identified to be significantly associated genomewide with coronary artery disease. However, the mechanisms that link ADAMTS-7 and coronary artery disease risk remain elusive. We have previously demonstrated that ADAMTS-7 promotes vascular smooth muscle cell migration and postinjury neointima formation via degradation of a matrix protein cartilage oligomeric matrix protein. Because delayed endothelium repair renders neointima and atherosclerosis plaque formation after vessel injury, we examined whether ADAMTS-7 also inhibits re-endothelialization.Methods And ResultsWire injury of the carotid artery and Evans blue staining were performed in Adamts7(-/-) and wild-type mice. Adamts-7 deficiency greatly promoted re-endothelialization at 3, 5, and 7 days after injury. Consequently, Adamts-7 deficiency substantially ameliorated neointima formation in mice at days 14 and 28 after injury in comparison with the wild type. In vitro studies further indicated that ADAMTS-7 inhibited both endothelial cell proliferation and migration. Surprisingly, cartilage oligomeric matrix protein deficiency did not affect endothelial cell proliferation/migration and re-endothelialization in mice. In a further examination of other potential vascular substrates of ADAMTS-7, a label-free liquid chromatography-tandem mass spectrometry secretome analysis revealed thrombospondin-1 as a potential ADAMTS-7 target. The subsequent studies showed that ADAMTS-7 was directly associated with thrombospondin-1 by its C terminus and degraded thrombospondin-1 in vivo and in vitro. The inhibitory effect of ADAMTS-7 on postinjury endothelium recovery was circumvented in Tsp1(-/-) mice.ConclusionsOur study revealed a novel mechanism by which ADAMTS-7 affects neointima formation. Thus, ADAMTS-7 is a promising treatment target for postinjury vascular intima hyperplasia.© 2015 American Heart Association, Inc.

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