A novel CD147 inhibitor, SP-8356, reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation

Kisoo Pahk,Kyung Won Kim,Won-Ki Kim,Sungeun Kim,Jong-Ik Hwang,Hyojin Noh,Chanmin Joung,Mi Jang,Hwa Young Song,Kihoon Han

doi:10.1186/s12967-019-2024-y

Kisoo Pahk, Kyung Won Kim + Show 8 more

Open Access

https://doi.org/10.1186/s12967-019-2024-y

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Abstract

BackgroundNeointimal 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.MethodsNeointimal 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.ResultsSP-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.ConclusionsThe 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.

Highlights

Neointimal hyperplasia and its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis
The present study investigated the ability of SP-8356 to inhibit vascular smooth muscle cell (VSMC) migration and arterial stiffness in this rat model characterized by neointimal hyperplasia
SP‐8356 disrupts the dimerization of Cluster of differentiation 147 (CD147) Dimerization of CD147 induces matrix metalloproteinase (MMP) expression and activation [14]

Summary

Introduction

Neointimal hyperplasia and its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis. Neointimal hyperplasia, defined as the thickening of the arterial intima with a narrowed arterial lumen space, is a key feature of early atherosclerotic lesions and in-stent restenosis [1, 2]. The key regulatory mechanism underlying neointimal hyperplasia is the phenotypic plasticity of vascular smooth muscle cells (VSMCs) [2]. Exposure of the vessels to injury or inflammatory stimuli results in VSMC switching to a synthetic phenotype. These synthetic VSMCs migrate to the intima from the media and contribute to the formation of neointimal hyperplasia [4]. Synthetic VSMCs build up neointima but may promote plaque vulnerability

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