Department of Surgery, Division of Vascular Surgery and Endovascular Services, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
College of Medicine, MD Program, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Mol Med Rep. 2020 Apr;21(4):1959-1964. doi: 10.3892/mmr.2020.10994. Epub 2020 Feb 20.
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. 17‑N‑allylamino‑17‑demethoxygeldanamycin (17‑AAG) and 17‑dimethylaminoethylamino‑17‑demethoxygeldanamycin (17‑DMAG) 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 post‑angioplasty IH formation. For proliferation, VSMCs were treated with serum‑free media (SFM), 17‑DMAG or 17‑AAG. 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, 17‑AAG or 17‑DMAG 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, 17‑DMAG in 20% pluronic gel delivered topically to the adventitia or intraluminal delivery of 17‑DMAG. After 14 days, arteries were fixed and sectioned for morphometric analysis. Data was analyzed using ANOVA or a student's t‑test. P<0.05 was considered to indicate a statistically significant difference. The results revealed that 17‑AAG and 17‑DMAG had no effect on cell viability. PDGF and fibronectin also increased VSMC proliferation and migration. Furthermore, both 17‑AAG and 17‑DMAG decreased cell migration and proliferation in all agonists. Topical adventitial treatment with 17‑DMAG 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 17‑DMAG may be utilized as an effective therapy to prevent restenosis after revascularization.
内膜增生（IH）是一种导致外周动脉疾病治疗后再狭窄的病理过程。热休克蛋白 90（HSP90）是一种调节蛋白质成熟的分子伴侣。HSP90 的激活导致细胞迁移和增殖增加。17-N-烯丙基-17-去甲氧基格尔德霉素（17-AAG）和 17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素（17-DMAG）是低毒的美国食品和药物管理局批准的 HSP90 抑制剂。本研究假设 HSP90 抑制可预测减少血管平滑肌细胞（VSMC）迁移和增殖。此外，局部 HSP90 抑制可能抑制血管成形术后 IH 的形成。对于增殖，用无血清培养基（SFM）、17-DMAG 或 17-AAG 处理 VSMCs。选择的增殖剂为 SFM、血小板衍生生长因子（PDGF）或纤维连接蛋白。三天后，测量增殖。对于迁移，用 SFM、17-AAG 或 17-DMAG 处理 VSMCs，SFM、PDGF 或纤维连接蛋白作为趋化剂。在大鼠的颈总动脉进行球囊损伤。本研究包括对照组、生理盐水对照组、20%普朗尼克凝胶局部施用于外膜的 17-DMAG 组或腔内递送 17-DMAG 组。14 天后，固定动脉并进行形态计量学分析。使用方差分析或学生 t 检验分析数据。P<0.05 被认为表示具有统计学意义的差异。结果显示，17-AAG 和 17-DMAG 对细胞活力没有影响。PDGF 和纤维连接蛋白也增加了 VSMC 的增殖和迁移。此外，在所有激动剂中，17-AAG 和 17-DMAG 均降低了细胞迁移和增殖。球囊动脉损伤后，17-DMAG 局部外膜治疗减少了 IH。HSP90 抑制剂抑制 VSMC 增殖和迁移，而不影响细胞活力。HSP90 抑制剂（DMAG）的局部治疗可减少动脉损伤后 IH 的形成。结论是，17-DMAG 可作为一种有效的治疗方法，用于防止血管再通后的再狭窄。
