Journal
CIRCULATION
Volume 131, Issue 13, Pages 1191-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.114.014072
Keywords
matrix metalloproteinases; neointima; vascular remodeling
Funding
- International Cooperation and Exchanges NSFC [81220108004]
- National Program on Key Basic Research Projects (973 Program) [2012CB518002]
- National Natural Science Foundation of the P.R. China [81070243, 81121061, 91339000]
- National Science Fund for distinguished Young Scholars [81225002]
- 111 Project of Chinese Ministry of Education [B07001]
- German Federal Ministry of Education and Research (BMBF)
- FP7 European Union project CVgenes@target [261123]
- Foundation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes) [12CVD02]
- German Federal Ministry of Education and Research [01KX1012, 01 EO 0901]
- Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Research in an Ageing Society [HA-215]
- British Heart Foundation [FS/13/2/29892] Funding Source: researchfish
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Background-ADAMTS-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 Results-Wire 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 labelfree 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. Conclusions-Our 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.
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