A Novel Drug SP-8356 Attenuates Neointimal Hyperplasia And With Its Related Arterial Stiffness Via Affecting CD147/MMP-9 Pathway In A Rat Atherosclerotic Carotid Artery

초록

Background and Aims: Neointimal hyperplasia and with its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis. CD147 plays important roles in neointimal hyperplasia through matrix metalloproteinase-9 (MMP-9) expression. Thus, CD147 can emerge as an effective therapeutic target for treatment of neointimal hyperplasia. We identified that a novel drug SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) could bind to CD147 which was involved in MMP-9 expression. We investigated the suppressive effects of a novel drug SP-8356 on neointimal hyperplasia and arterial stiffness using an atherosclerotic rat model. Methods: Atherosclerosis was induced in Sprague-Dawley rats by partial ligation of the right carotid artery coupled with atherogenic diet and vitamin D injection. The elasticity of blood vessels was assessed by measuring pulse wave velocity using Doppler ultrasonography. After sacrifice, the blood vessels were stained with hematoxylin/eosin or antibodies against α-smooth muscle-actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), collagen type III, and MMP-9. Results: SP-8356 reduced neointimal hyperplasia and prevented the atherosclerosis-evoked decrease of vascular elasticity. SP-8356 increased the expression of SM-MHC, but decreased the expressions of collagen type III, and MMP-9 in the neointima region. Unlike SP-8356, however, rosuvastatin did not alter the expressions of SM-MHC and MMP-9. Furthermore, rosuvastatin did not prevent the atherosclerosis-induced decrease of vascular elasticity. The present study demonstrated that unlike rosuvastatin, SP-8356 reduced not only neointimal hyperplasia but improved arterial stiffness in atherosclerotic carotid arteries. Conclusions: SP-8356 exhibited anti-atherosclerotic effect by suppressing CD147/MMP-9 pathway. Therefore, SP-8356 could be a promising therapeutic drug for vascular remodeling disorders involving neointimal hyperplasia and arterial stiffness.