A novel drug SP-8356 targeting CD147 suppresses pathological vascular remodeling via affecting vascular smooth muscle cell phenotype expression in atherosclerotic rat model

초록

Background and Aims: The switching of vascular smooth muscle cell (VSMC) phenotype plays key roles in neointimal hyperplasia and its related arterial stiffness. 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 the switching of VSMC phenotype and may therefore be an effective target for the treatment of neointimal hyperplasia. Here, we investigated whether a novel drug SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) targeting CD147 inhibitor could affects VSMC phenotype expression and inhibit neoitimal hyperplasia in atherosclerotic rat model. Methods: The A10 VMSC cell lines were used for in-vitro experiment. Neointimal hyperplasia was generated in Sprague-Dawley rats by partial ligation of the right carotid artery combined with an atherogenic diet. Rosuvastatin was used for positive control drug. Rats were subdivided into vehicle and SP-8356 (50 mg/kg) groups. The drug was administrated via intraperitoneal injections for 4 weeks. Arterial stiffness was assessed by measuring pulse wave velocity using Doppler ultrasonography before sacrifice. Results: SP-8356 suppressed CD147 dimerization thereby reducing MMP-9 activity, synthetic VSMC phenotype expression, and VSMC migration. SP-8356 also reduced neointimal hyperplasia and improved arterial stiffness in animal model. SP-8356 enhanced the expression of smooth muscle myosin heavy chain, but decreased the collagen type III and MMP-9 expression in the neointimal area. Conclusions: SP-8356 affects VSMC phenotype modulation thereby reducing neointimal hyperplsaisa. Thus, SP-8356 could be a promising therapeutic drug for vascular remodeling disorders related with neointimal hyperplasia and arterial stiffness.