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Copper Chelation Represses the Vascular Response to Injury

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Copper Chelation Represses the Vascular Response to Injury Copper chelation represses the vascular response to injury Lazar Mandinov*†, Anna Mandinova*†, Stanimir Kyurkchiev‡, Dobroslav Kyurkchiev‡, Ivan Kehayov‡, Vihren Kolev*, Raffaella Soldi*, Cinzia Bagala*, Ebo D. de Muinck§, Volkhard Lindner*, Mark J. Post¶, Michael Simons§, Stephen Bellum*, Igor Prudovsky*, and Thomas Maciag*ʈ *Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074; ‡Institute for Immunology, Sofia 1113, Bulgaria; ¶Department of Physiology, University of Maastricht, 6200MD, Maastricht, The Netherlands; and §Department of Medicine, Dartmouth Medical School, Hanover, NH 03756 Communicated by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, April 3, 2003 (received for review January 23, 2003) The induction of an acute inflammatory response followed by the sequence. Because it is well established that the IL-1 and FGF release of polypeptide cytokines and growth factors from periph- prototypes function in the extracellular compartment as ligands eral blood monocytes has been implicated in mediating the re- for high-affinity cell-surface receptors (11, 13), the identification sponse to vascular injury. Because the Cu2؉-binding proteins IL-1␣ of the mechanism(s) used by the IL-1 and FGF prototypes for and fibroblast growth factor 1 are exported into the extracellular nonclassical release could potentially yield new insight into compartment in a stress-dependent manner by using intracellular proinflammatory and angiogenic disorders. Cu2؉ to facilitate the formation of S100A13 heterotetrameric The appearance of IL-1␣ and FGF1 in the extracellular complexes and these signal peptideless polypeptides have been compartment is regulated by convergent yet distinct nonclassical implicated as regulators of vascular injury in vivo, we examined the export pathways induced by cellular stress (17, 18). Both IL-1␣ ability of Cu2؉ chelation to repress neointimal thickening in re- (19) and FGF1 (20) use intracellular Cu2ϩ to force the assembly sponse to injury. We observed that the oral administration of the of a multiprotein complex near the inner surface of the plasma Cu2؉ chelator tetrathiomolybdate was able to reduce neointimal membrane (19, 20). Although both IL-1␣ and FGF1 form thickening after balloon injury in the rat. Interestingly, although Cu2ϩ-dependent heterotetrameric complexes with S100A13 to immunohistochemical analysis of control neointimal sections ex- facilitate their release, the FGF1 release pathway also requires hibited prominent staining for MAC1, IL-1␣, S100A13, and the the function of the extravesicular domain of synaptotagmin acidic phospholipid phosphatidylserine, similar sections obtained (Syt)1 for export (21). Interestingly, the overexpression of from tetrathiomolybdate-treated animals did not. Further, adeno- S100A13 overcomes the requirement for stress-induced tran- viral gene transfer of the IL-1 receptor antagonist during vascular scription for export of IL-1␣ (19) and FGF1 (22), and it is known injury also significantly reduced the area of neointimal thickening. that both FGF1 (23) and IL-1␣ (19) exhibit molten globule Our data suggest that intracellular copper may be involved in character, which may facilitate the ability of both IL-1␣ and mediating the response to injury in vivo by its ability to regulate FGF1 to associate with and traverse the plasma membrane. It is the stress-induced release of IL-1␣ by using the nonclassical export also interesting to note that IL-1␣, FGF1, Syt1, and S100A13 are mechanism employed by human peripheral blood mononuclear Cu2ϩ-binding proteins (20) and are able to associate with cells in vitro. phosphatidylserine (pS), an acidic phospholipid that is known to translocate from the inner to the outer surface of the plasma phosphatidylserine ͉ interleukin 1 ͉ restenosis ͉ tetrathiomolybdate ͉ membrane (24). Further, studies in both murine NIH 3T3 cells fibroblast growth factor and human U937 cells have demonstrated that the stress-induced IL-1␣ (19) and FGF1 (20) release pathways are sensitive to inhibition by the Cu2ϩ chelator tetrathiomolybdate (TTM), he elucidation of the pathways involved in the regulation of ϩ Tthe vascular response to injury is critical for the management suggesting that intracellular Cu2 may play an important role in of human diseases in which the pathology may be regulated by the regulation of these pathways in vivo. It is well established that Cu2ϩ is not only a potent inducer of stress-induced endothelial and vascular smooth muscle cell ϩ responses. Although a variety of polypeptide growth factors and angiogenesis in vivo (25), but studies with arterial Cu2 cuffs and ϩ cytokines have been implicated as mediators of the vascular stents have also implicated Cu2 as a promoter of the arterial response to injury (1–5), our current understanding involves a response to injury (26). Because (i) TTM has been suggested to fundamental role for the migration of peripheral blood mono- be efficacious in the clinical management of human cancer (27), nuclear (PBM) cells into sites of injury as a delivery system for (ii) TTM is able to significantly inhibit NF-␬B activity as a these biological response modifiers as regulators of both the component of its antiangiogenic activity in vivo (28), and (iii) inflammatory and angiogenic responses (6, 7). IL-1 is an important regulator of NF-␬B activity (29), we Prior studies have suggested that members of the IL-1 and questioned whether TTM could be used to limit the recruitment fibroblast growth factor (FGF) (8, 9) gene families may signif- of mononuclear cells in response to vascular injury in vivo by icantly contribute to vessel-wall pathology in response to injury. restricting the export of IL-1␣. We report that the induction of The IL-1 and FGF gene families are composed of at least 10 and moderate copper deficiency by the oral administration of TTM 23 members, respectively (10–13), and membership is defined by impairs neointimal thickening and significantly reduces the structural homology with the prototype members of each gene expression of IL-1␣ and S100A13. In addition, we used a family, namely IL-1␣͞IL-1␤ and FGF1͞FGF2. Although the IL-1 and FGF prototypes exhibit limited primary sequence homology (14), these prototype polypeptides are viewed as Abbreviations: PBM, peripheral blood mononuclear; FGF, fibroblast growth factor; pS, phosphatidylserine; TTM, tetrathiomolybdate; IRAP, IL-1 receptor antagonist crystallographic homologs (15). Furthermore, the IL-1 and FGF protein; PMA, phorbol 12-myristate 13-acetate; PECAM, platelet-endothelial cell adhesion prototypes do not contain classical signal peptide sequences to molecule. direct their export through the endoplasmic reticulum-Golgi †L.M. and A.M. contributed equally to this work. apparatus (16), and although only 3 of the 23 FGF genes lack this ʈTo whom correspondence should be addressed at: Maine Medical Center Research Insti- feature, 8 of the 10 IL-1 genes lack a classical signal peptide tute, 81 Research Drive, Scarborough, ME 04074. E-mail: [email protected]. 6700–6705 ͉ PNAS ͉ May 27, 2003 ͉ vol. 100 ͉ no. 11 www.pnas.org͞cgi͞doi͞10.1073͞pnas.1231994100 Downloaded by guest on September 29, 2021 monoclonal antibody that recognizes the acidic phospholipid pS lamina (EEL) area, the internal elastic lamina (IEL) area, and and demonstrated that TTM is also able to significantly limit the the luminal area were measured. Other areas were calculated as: appearance of pS after vascular injury in vivo. Last, the somatic medial area ϭ EEL area Ϫ IEL area; neointimal area ϭ IEL gene transfer of the IL-1 receptor antagonist protein (IRAP) area Ϫ luminal area; and neointima-to-medium ratio ϭ neoin- also significantly reduces the response to vascular injury. These timal area͞medial area. All variables are expressed as the data suggest that members of the IL-1 gene family may play a mean Ϯ SEM, and the Student’s t test was used to examine the prominent role in restenosis in vivo. differences between the experimental groups. A value of P Յ 0.05 was considered significant. Methods Cell Culture and Immunoblot Analysis. Human PBM cells were Generation and Characterization of Murine Monoclonal Antibody 1H6. isolated by Fico͞Lite density gradient centrifugation from hep- To generate monoclonal antibodies against pS, BALB͞c mice arinized blood of healthy donors. Mononuclear cells were fur- were immunized with liposomes containing 70% pS and 30% ther isolated by adherence on tissue-culture dishes for2hand phosphatidylglycerol. Liposomes were resuspended in ethanol maintained in RPMI medium 1640 (Sigma) containing 10% and injected five times i.p. with an interval of 3 weeks between FBS. Mononuclear cells were activated with 10 ng͞ml of phorbol injections. Hybridoma selection was performed as described 12-myristate 13-acetate (PMA; Sigma) for 24 h before each (34). Approximately 14 days postfusion, supernatants from wells experiment. Before heat shock (2 h at 42°C), the mononuclear with proliferating hybrid cells were collected and tested for the cells were plated on fibronectin (10 mg͞cm3)-coated cell-culture presence of anti-pS antibodies. The reactivity of the selected dishes. Briefly, IL-1␣ from the conditioned medium was resolved antibody was established by screening hybridoma supernatants by Cu2ϩ-affinity chromatography (Hi Trap, Amersham Pharma- on pS, cholesterol, phosphatidylethanolamine, and phosphati- cia), eluted with 60 mM imidazole, resolved by 15% acrylamide dylcholine (Avanti Polar Lipids) either immobilized
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