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Am J Pathol. 2012 Oct;181(4):1151-7. doi: 10.1016/j.ajpath.2012.06.023. Epub 2012 Jul 27.

Mitochondrial heat shock protein-90 modulates vascular smooth muscle cell survival and the vascular injury response in vivo.

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  • 1Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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.

Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PMID:
22841823
[PubMed - indexed for MEDLINE]
PMCID:
PMC3463635
Free PMC Article

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