Copper chelation represses the vascular response to injury

Abstract

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 Cu 2؉ -binding proteins IL-1␣ and fibroblast growth factor 1 are exported into the extracellular compartment in a stress-dependent manner by using intracellular Cu 2؉ 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 Cu 2؉ chelation to repress neointimal thickening in response to injury. We observed that the oral administration of the Cu 2؉ 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-1␣, 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-1␣ by using the nonclassical export mechanism employed by human peripheral blood mononuclear cells in vitro.phosphatidylserine ͉ interleukin 1 ͉ restenosis ͉ tetrathiomolybdate ͉ fibroblast growth factor

Leishmaniadisease development depends on the presence of apoptotic promastigotes in the virulent inoculum

“…In addition, PS was detected by using an anti-PS mAb (Clone 1H6, IgG, Biomol, Hamburg, Germany; ref. 15). Purified mouse IgG (Sigma, Taufkirchen, Germany) was used as negative control.…”

“…Protein S acts by binding with its glutamic acid-rich positively charged N terminus to the negatively charged PS in a Ca 2ϩ -dependent manner (13,14). Moreover, a mAb was developed recognizing PS (15). Interestingly, recent in vivo experiments showed disease exacerbation when Leishmania were injected together with apoptotic cells.…”

Regeneration of the Heart in Diabetes by Selective Copper Chelation

“…ECM Cu trapping could help to explain the different location of tissue damage in diabetes compared with Wilson's disease. Oral administration of the Cu chelator tetrathiomolybdate reportedly decreased neointimal thickening after balloon injury in the rat (46). Impaired glucose tolerance occurs in conditions other than diabetes, notably atherosclerosis, hypertension, obesity, and normal aging, all of which are accompanied by increased tissue advanced glycation end products (47).…”

Sphingosine kinase 1 is a critical component of the copper-dependent FGF1 export pathway

“…Although the biological significance of SK1 as a component of the FGF1 multiprotein release complex is not fully understood, the biological relevance of copper as a mediator of the assembly of this complex was determined. Indeed, the response to injury in the rat aorta is sensitive to TM treatment by its ability to repress the release of IL1α, FGF1, and S100A13, as well as to reduce the appearance of pS on the surface of cells [60]. Because S1P is a mediator of angiogenic response in vivo [10,54,61], it is interesting that SK1, which is responsible for the production of S1P, is a component of the proangiogenic FGF1 release complex.…”