A disintegrin and metalloproteinase 15 contributes to atherosclerosis by mediating endothelial barrier dysfunction via src family kinase activity

Chongxiu Sun, MacK H. Wu, Eugene S Lee, Sarah Y. Yuan

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

OBJECTIVE-: Endothelium dysfunction is an initiating factor in atherosclerosis. A disintegrin and metalloproteinase 15 (ADAM 15) is a multidomain metalloprotease recently identified as a regulator of endothelial permeability. However, whether and how ADAM15 contributes to atherosclerosis remains unknown. METHODS AND RESULTS-: Genetic ablation of ADAM15 in apolipoprotein E-deficient mice led to a significant reduction in aortic atherosclerotic lesion size (by 52%), plaque macrophage infiltration (by 69%), and smooth muscle cell deposition (by 82%). In vitro studies implicated endothelial-derived ADAM15 in barrier dysfunction and monocyte transmigration across mouse aortic and human umbilical vein endothelial cell monolayers. This role of ADAM15 depended on intact functioning of the cytoplasmic domain, as evidenced in experiments with site-directed mutagenesis targeting the metalloprotease active site (E349A), the disintegrin domain (Arginine-Glycine- Aspartic acid→Threonine-Aspartic acid-Aspartic acid), or the cytoplasmic tail. Further investigations revealed that ADAM15-induced barrier dysfunction was concomitant with dissociation of endothelial adherens junctions (vascular endothelial [VE]-cadherin/γ-catenin), an effect that was sensitive to Src family kinase inhibition. Through small interfering RNA-mediated knockdown of distinct Src family kinase members, c-Src and c-Yes were identified as important mediators of these junctional effects of ADAM15. CONCLUSION-: These results suggest that endothelial cell-derived ADAM15, signaling through c-Src and c-Yes, contributes to atherosclerotic lesion development by disrupting adherens junction integrity and promoting monocyte transmigration.

Original languageEnglish (US)
Pages (from-to)2444-2451
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number10
DOIs
StatePublished - Nov 2012

Keywords

  • endothelial dysfunction
  • inflammation
  • intercellular junctions
  • metalloproteinase
  • vascular permeability

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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