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

J Transl Med. 2019 Aug 20;17(1):274. doi: 10.1186/s12967-019-2024-y.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Arterial stiffness; Atherosclerosis; CD147; MMP-9; Matrix metalloproteinase; Neointimal hyperplasia; Vascular smooth muscle cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basigin / antagonists & inhibitors*
  • Basigin / metabolism
  • Bicyclic Monoterpenes / chemistry
  • Bicyclic Monoterpenes / pharmacology*
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Carotid Arteries / pathology*
  • Carotid Arteries / physiopathology*
  • Cell Line
  • Cells, Cultured
  • Collagen Type III / metabolism
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Drug Discovery
  • Hyperplasia
  • Ligation
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Muscle, Smooth, Vascular / metabolism
  • Neointima / pathology*
  • Phenotype
  • Rats, Sprague-Dawley
  • Vascular Stiffness / drug effects*

Substances

  • Bicyclic Monoterpenes
  • Bridged Bicyclo Compounds
  • Collagen Type III
  • SP-8356
  • Basigin
  • Matrix Metalloproteinase 9