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


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.


CONCLUSIONS
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.
Departments of Molecular Pharmacology and Physiology and Surgery, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
Chongxiu
C
Sun
Mack H
MH
Wu
Eugene S
ES
Lee
Sarah Y
SY
Yuan
D051722:ADAM Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology*; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D051575:Proto-Oncogene Proteins c-yes / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000081247:CSK Tyrosine-Protein Kinase; D051575:Proto-Oncogene Proteins c-yes; D019061:src-Family Kinases; C000631346:CSK protein, human; D051722:ADAM Proteins; C490902:Adam15 protein, mouse