Abstract 19545: Enhancing Endothelial Healing Post-Arterial Injury and Stent Implantation: Efficacy of Heat Shock Protein 27 as a Vascular Protective Therapy
Previously we demonstrated that Heat shock protein 27 (HSP27) has atheroprotective effects [Circ Res 2008].PURSPOSE: To determine if HSP27 may provide an effective strategy to enhance re-endothelialization of injured vessels, including stented arteries. 72 male and female wild type (WT) and HSP27 over-expressing (HSP27o/e) mice were fed a normal chow and subjected to femoral artery wire injury before being euthanized on days 7, 14 or 28. The circulating CD45dim/Sca-1+/Flk-1+ endothelial progenitor cells (EPCs) from HSP27o/e mice increased 2.8- and 2.7-fold on days 3 and 7 post injury compared to WT (p<0.05). Re-endothelialization increased by 67% and 65% in HSP27o/e males and females on day 7 relative to WT mice (e.g., males: 78.4±7.5% vs. 47.0±6.9%; females: 80.9±4.9% vs. 48.9±4.6%; p<0.05 for both sexes). By 28 days the intima:media ratio was reduced by 52% and 75% in male and female HSP27o/e mice respectively (e.g., males: 0.34±0.06 vs. 0.71±0.14 and females: 0.14±0.05 vs. 0.57±0.06; p<0.05 for both sexes). To further illustrate the therapeutic potential of HSP27, we synthesized recombinant human HSP27 (rHSP27) in our lab. Pre-treatment of HUVECs with the rHSP27 resulted in increased migration compared with non-treated cells. Next, we coated stents with rHSP27 and cultured human EPCs with the coated stents in vitro. The number of adherent cells (per mm2 of stent) to rHSP27-coated stents increased in a dose-dependent manner (e.g., control: 51.5±13.5; rHSP27 5μg/ml: 105.1±19.1; rHSP27 50μg/ml: 199.9±45.0). Finally, rHSP27-coated stents were inserted into rabbit carotid arteries and increased re-endothelialization by 43.7% and 35.7% at day-7 post stenting compared to bare metal stents (BMS) and vehicle-coated stents (VS) (e.g., BMS, 46.7±3.8%, VS, 49.4±3.2%, rHSP27, 67.1±8.1%, p<0.05).
Conclusions: Both in vitro and in vivo HSP27 has salutary effects on the endothelium, particular after arterial injury / stenting. These effects are particularly important given that some current drug eluting stents have toxic effects on the endothelium and may pre-dispose patients to stent thrombosis. Future efforts to combine HSP27 with more anti-inflammatory drugs may result in the production of a DES that is efficacious and shows a superior safety profile.
- © 2010 by American Heart Association, Inc.