José Hermida, MD,PhD, University of Navarra, Center for Applied Medical Research (CIMA), Laboratory of Thrombosis and Haemostasis, Pío XII 55, Pamplona 31008, Spain, Tel.: +34948194700×3027, Fax: +34948194716, E-mail:
Thromb Haemost. 2017 Aug 30;117(9):1722-1729. doi: 10.1160/TH17-02-0108. Epub 2017 Jul 27.
Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. The heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. By using murine models, we aimed to test the hypothesis that overexpressing Hsp70 with CM-695, a first in class dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. Intraperitoneal (i. p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [p=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs 39.0 minutes (min) in the control group (CG), p=0.008, n≥10] and ferric chloride (OT: 14.7 vs 9.2 min in the CG, p=0.032, n≥10) models. I.p. 80 mg/kg CM-695 (n≥9) and intravenous 3 mg/kg rivaroxaban (n≥8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs 7.5 min in the CG, n≥10]. However, BT was dramatically increased by rivaroxaban (30.0 vs 13.7 min in the CG, p=0.001, n=10). In conclusion, CM-695 is a new antithrombotic small molecule devoid of bleeding risk that may be envisioned as a useful clinical tool.
抗血栓药物针对凝血因子。它们的使用与出血风险增加有关。需要更安全的药物。热休克蛋白 70（Hsp70）具有抗血栓特性，不会影响出血。我们使用鼠模型旨在测试以下假设：使用第一类组蛋白去乙酰化酶 6 和磷酸二酯酶 9 的双重抑制剂 CM-695 过表达 Hsp70 可预防血栓形成，同时不改变出血倾向。CM-695 用于诱导 Hsp70 过表达。过表达 Hsp70 的小鼠接受了三种血栓形成触发程序。三氯化铁颈动脉模型用于比较 CM-695 和直接口服抗凝剂利伐沙班的抗血栓作用。小鼠尾切断模型用于比较 CM-695 或利伐沙班给药后的出血倾向。腹腔内（i.p.）20 mg/kg CM-695 可显著增加小鼠主动脉组织中的 Hsp70 表达。这种治疗可延迟胶原/肾上腺素（p=0.04[对数秩检验]，n=10）、玫瑰红/激光（中位血管闭塞时间（OT）：在对照组（CG）中为 58.6 分钟 vs 39.0 分钟，p=0.008，n≥10）和三氯化铁（OT：在 CG 中为 14.7 分钟 vs 9.2 分钟，p=0.032，n≥10）模型中的血栓形成。i.p.80 mg/kg CM-695（n≥9）和静脉内 3 mg/kg 利伐沙班（n≥8）可显著延迟血栓形成。CM-695 不会引起出血[中位出血时间（BT）：在 CG 中为 8.5 分钟 vs 7.5 分钟，n≥10]。然而，利伐沙班显著增加了 BT（在 CG 中为 30.0 分钟 vs 13.7 分钟，p=0.001，n=10）。总之，CM-695 是一种新型抗血栓小分子化合物，没有出血风险，可作为一种有用的临床工具。
