Publications (2)9.66 Total impact
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Article: Mitochondrial heat shock protein-90 modulates vascular smooth muscle cell survival and the vascular injury response in vivo.
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ABSTRACT: The healing response of blood vessels from the vascular injury induced by therapeutic interventions is characterized by increased cellularity and tissue remodeling. Frequently, this leads to intimal hyperplasia and lumen narrowing, with significant clinical sequelae. Vascular smooth muscle cells are the primary cell type involved in this process, wherein they express a dedifferentiated phenotype that transiently resembles neoplastic transformation. Recent studies have highlighted the role of mitochondrial proteins, such as the molecular chaperone heat shock protein-90 (Hsp90), in promoting cancer cell survival, which leads to new candidate chemotherapeutic agents for neoplastic disease. Herein, we identify mitochondrial Hsp90 as a key modulator of the vascular injury response. Hsp90 expression is up-regulated in injured arteries and colocalizes with the apoptosis inhibitor, survivin, in vascular smooth muscle cell in vitro and in vivo. By using a proteomic approach, we demonstrate that targeted disruption of mitochondrial Hsp90 chaperone function in vascular smooth muscle cell leads to loss of cytoprotective client proteins (survivin and Akt), induces mitochondrial permeability, and leads to apoptotic cell death. Hsp90 targeting using a cell-permeable peptidomimetic agent resulted in marked attenuation of neointimal lesions in a murine arterial injury model. These findings suggest that mitochondrial Hsp90 chaperone function is an important regulator of intimal hyperplasia and may have implications for molecular strategies that promote the long-term patency of cardiovascular interventions.American Journal Of Pathology 07/2012; 181(4):1151-7. · 4.89 Impact Factor -
Article: Molecular Identification of the Cross-reacting Epitope on αMβ2 Integrin I Domain Recognized by Anti-αIIbβ3 Monoclonal Antibody 7E3 and Its Involvement in Leukocyte Adherence
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ABSTRACT: The monoclonal antibody (mAb) 7E3 directed to the platelet integrin αIIbβ3 was tested for its cross-reactivity with the homologous leukocyte integrin αMβ2. Nested recombinant fragments of αM I domain were expressed as glutathioneS-transferase fusion proteins and analyzed for antibody recognition. In enzyme-linked immunosorbent assay, mAb 7E3 bound αM I domain fragments containing the amino-terminal sequence Cys128–Ser172, whereas the carboxyl-terminal region Leu173–Pro291 was ineffective. A synthetic peptide designated R1.1 and duplicating the αM sequence G127CPQEDSDIAFLIDGSGSIIPHDF150 bound mAb 7E3. In contrast, the adjacent αM region F150RRMKEFVSTVMEQLKKSKTLFS172 or a control peptide with a scrambled R1.1 sequence was not recognized by mAb 7E3. Binding of mAb 7E3 to αM I domain blocked monocyte and neutrophil adhesion to immobilized fibrinogen and fibrinogen-dependent leukocyte-endothelium bridging, indistinguishably from bona fide anti-β2 mAb IB4. In contrast, leukocyte binding to stable transfectants expressing intercellular adhesion molecule-1 was not affected by mAb 7E3. Balloon-mediated injury of iliofemoral arteries in rabbits resulted in prominent deposition of fibrinogen and increased monocyte adhesion to the injured vessel, in a reaction inhibited by mAb 7E3, but unaffected by control mAb 14E11. Through its cross-reactivity between αIIbβ3 and αMβ2, mAb 7E3 may initiate a new class of integrin antagonists, capable of simultaneously targeting platelet and leukocyte adhesion mechanisms in vascular injury.Journal of Biological Chemistry 08/1998; 273(32):20372-20377. · 4.77 Impact Factor
