Institute for Inflammation Control, Korea University, Seoul, South Korea.
Department of Neuroscience, Korea University College of Medicine, 126-1, Anam-Dong 5-Ga, Seongbuk-Gu, Seoul, 136-705, South Korea.
J Transl Med. 2019 Aug 20;17(1):274. doi: 10.1186/s12967-019-2024-y.
Neointimal hyperplasia and its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis. Cluster of differentiation 147 (CD147), a member of the immunoglobulin super family that induces the expression of matrix metalloproteinase-9 (MMP-9) by dimerization, may play important roles in neointimal hyperplasia and may therefore be an effective target for the treatment of this condition. Here, we investigated whether a novel CD147 inhibitor SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation.
Neointimal hyperplasia was induced in Sprague-Dawley rats by partial ligation of the right carotid artery combined with a high fat diet and vitamin D injection. Rats were subdivided into vehicle, SP-8356 (50 mg/kg), and rosuvastatin (10 mg/kg) groups. The drugs were administrated via intraperitoneal injections for 4 weeks. The elasticity of blood vessels was assessed by measuring pulse wave velocity using Doppler ultrasonography before sacrifice. Histomolecular analysis was carried out on harvested carotid arteries.
SP-8356 significantly reduced MMP activity by inhibiting CD147 dimerization. SP-8356 reduced neointimal hyperplasia and prevented the deterioration of vascular elasticity. SP-8356 had a greater inhibitory effect on neointimal hyperplasia than did rosuvastatin. Furthermore, rosuvastatin did not improve vascular elasticity. SP-8356 increased the expression of smooth muscle myosin heavy chain (SM-MHC), but decreased the expression of collagen type III and MMP-9 in the neointimal region. In contrast to SP-8356, rosuvastatin did not alter the expression of SM-MHC or MMP-9.
The ability of SP-8356 to reduce neointimal hyperplasia and improve arterial stiffness in affected carotid artery suggests that SP-8356 could be a promising therapeutic drug for vascular remodeling disorders involving neointimal hyperplasia and arterial stiffness.
新生内膜增生及其相关的动脉僵硬是动脉粥样硬化和支架内再狭窄的关键病理生理特征。CD147（分化群 147）是免疫球蛋白超家族的成员，通过二聚化诱导基质金属蛋白酶-9（MMP-9）的表达，在新生内膜增生中可能发挥重要作用，因此可能成为治疗这种疾病的有效靶点。在这里，我们研究了一种新型 CD147 抑制剂 SP-8356（（1S，5R）-4-（3,4-二羟基-5-甲氧基苯乙烯基）-6,6-二甲基双环[3.1.1]庚-3-烯-2-酮）是否可以减少部分颈动脉结扎大鼠模型中的新生内膜增生和动脉僵硬。
通过右颈动脉部分结扎联合高脂肪饮食和维生素 D 注射诱导 Sprague-Dawley 大鼠新生内膜增生。大鼠分为对照组、SP-8356（50mg/kg）组和罗苏伐他汀（10mg/kg）组。通过腹腔注射给药 4 周。在牺牲前，使用多普勒超声测量脉搏波速度来评估血管的弹性。对采集的颈动脉进行组织分子分析。
SP-8356 通过抑制 CD147 二聚化显著降低 MMP 活性。SP-8356 减少了新生内膜增生并防止了血管弹性的恶化。SP-8356 对新生内膜增生的抑制作用强于罗苏伐他汀。此外，罗苏伐他汀不能改善血管弹性。SP-8356 增加了平滑肌肌球蛋白重链（SM-MHC）的表达，但减少了新生内膜区域的胶原 III 型和 MMP-9 的表达。与 SP-8356 相反，罗苏伐他汀没有改变 SM-MHC 或 MMP-9 的表达。
SP-8356 降低受影响颈动脉新生内膜增生和改善动脉僵硬的能力表明，SP-8356 可能成为一种有前途的治疗药物，用于涉及新生内膜增生和动脉僵硬的血管重塑障碍。
