ABSTRACT
Intimal hyperplasia (IH) is a pathologic process that leads to restenosis after treatment for peripheral arterial disease. Heat shock protein 90 (HSP90) is a molecular chaperone that regulates protein maturation. Activation of HSP90 results in increased cell migration and proliferation. 17Nallylamino17demethoxygeldanamycin (17AAG) and 17dimethylaminoethylamino17demethoxygeldanamycin (17DMAG) are low toxicity Food and Drug Association approved HSP90 inhibitors. The current study hypothesized that HSP90 inhibition was predicted to reduce vascular smooth muscle cell (VSMC) migration and proliferation. In addition, localized HSP90 inhibition may inhibit postangioplasty IH formation. For proliferation, VSMCs were treated with serumfree media (SFM), 17DMAG or 17AAG. The selected proliferative agents were SFM, platelet derived growth factor (PDGF) or fibronectin. After three days, proliferation was measured. For migration, VSMCs were treated with SFM, 17AAG or 17DMAG with SFM, PDGF or fibronectin as chemoattractants. Balloon injury to the carotid artery was performed in rats. The groups included in the present study were the control, saline control, 17DMAG in 20% pluronic gel delivered topically to the adventitia or intraluminal delivery of 17DMAG. After 14 days, arteries were fixed and sectioned for morphometric analysis. Data was analyzed using ANOVA or a student's ttest. P<0.05 was considered to indicate a statistically significant difference. The results revealed that 17AAG and 17DMAG had no effect on cell viability. PDGF and fibronectin also increased VSMC proliferation and migration. Furthermore, both 17AAG and 17DMAG decreased cell migration and proliferation in all agonists. Topical adventitial treatment with 17DMAG after balloon arterial injury reduced IH. HSP90 inhibitors suppressed VSMC proliferation and migration without affecting cell viability. Topical treatment with a HSP90 inhibitor (DMAG) decreased IH formation after arterial injury. It was concluded that 17DMAG may be utilized as an effective therapy to prevent restenosis after revascularization.