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

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.

• Authors: Kisoo Pahk, Hyojin Noh, Chanmin Joung, Mi Jang, Hwa Young Song, Kyung Won Kim, Kihoon Han, Jong-Ik Hwang, Sungeun Kim, Won-Ki Kim
• Journal: Journal of translational medicine (J Transl Med) Vol. 17 Issue 1 Pg. 274 (08 20 2019) ISSN: 1479-5876 [Electronic] England
• PMID: 31429778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Basigin (antagonists & inhibitors, metabolism)
• Bicyclic Monoterpenes (chemistry, pharmacology)
• Bridged Bicyclo Compounds (chemistry, pharmacology)
• Carotid Arteries (pathology, 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)