Heat shock protein 27 attenuates neointima formation and accelerates reendothelialization after arterial injury and stent implantation: importance of vascular endothelial growth factor up-regulation.

Elevated serum heat shock protein 27 (HSP27) levels are atheroprotective; however, the role of HSP27 after arterial injury is unknown. Human endothelial progenitor cells (EPCs) were treated with recombinant (r)HSP27 (50 μg/ml) or its inactive C1 terminus, and gene expression was characterized before functional studies were performed in vitro and in vivo. Vascular endothelial growth factor (VEGF) was markedly up-regulated by rHSP27 (10- and 6-fold increases in mRNA and secretion, respectively). Pretreatment of EPCs with rHSP27 resulted in a 60% reduction in reendothelialization (RE) time in a scratch assay, an effect that was blocked with VEGF-neutralizing antibodies. Mice overexpressing HSP27 demonstrated more robust mobilization of EPCs at the time of arterial injury, as well as a 67% increase in RE and a 45% reduction in neointima (NI) formation at 28 d. Implantation of rHSP27-eluting stents in rabbit carotid arteries resulted in a marked improvement in RE at 7 and 28 d and transient attenuation of NI formation by 42% at 7 d. Hence, extracellular HSP27 up-regulated VEGF and improved EPC migration in vitro. Augmented systemic or local levels of HSP27 markedly improved RE after vascular injury, an effect that is of particular relevance to the safety profile of vascular stents.