Copper chelation represses the vascular response to injury.
The induction of an acute inflammatory response followed by the release of polypeptide cytokines and growth factors from peripheral blood monocytes has been implicated in mediating the response to vascular injury. Because the Cu2+-binding proteins IL-1alpha and fibroblast growth factor 1 are exported into the extracellular compartment in a stress-dependent manner by using intracellular Cu2+ to facilitate the formation of S100A13 heterotetrameric complexes and these signal peptideless polypeptides have been implicated as regulators of vascular injury in vivo, we examined the ability of Cu2+ chelation to repress neointimal thickening in response to injury. We observed that the oral administration of the Cu2+ chelator tetrathiomolybdate was able to reduce neointimal thickening after balloon injury in the rat. Interestingly, although immunohistochemical analysis of control neointimal sections exhibited prominent staining for MAC1, IL-1alpha, S100A13, and the acidic phospholipid phosphatidylserine, similar sections obtained from tetrathiomolybdate-treated animals did not. Further, adenoviral gene transfer of the IL-1 receptor antagonist during vascular injury also significantly reduced the area of neointimal thickening. Our data suggest that intracellular copper may be involved in mediating the response to injury in vivo by its ability to regulate the stress-induced release of IL-1alpha by using the nonclassical export mechanism employed by human peripheral blood mononuclear cells in vitro.
Mandinov
Lazar
L
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough 04074, USA.
Mandinova
Anna
A
Kyurkchiev
Stanimir
S
Kyurkchiev
Dobroslav
D
Kehayov
Ivan
I
Kolev
Vihren
V
Soldi
Raffaella
R
Bagala
Cinzia
C
de Muinck
Ebo D
ED
Lindner
Volkhard
V
Post
Mark J
MJ
Simons
Michael
M
Bellum
Stephen
S
Prudovsky
Igor
I
Maciag
Thomas
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008982:Molybdenum / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D002614:Chelating Agents; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin