Abstract
Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.
Highlights
Atherosclerosis is a major cause of mortality and morbidity worldwide associated with characteristic clinical symptoms, myocardial infarction, and stroke [1,2]
matrix metalloproteinase-9 (MMP-9) facilitates monocyte/macrophage infiltration into plaques through extracellular matrix (ECM) degradation and chemokine modulation, which contributes to increased burden of inflammation, thereby promoting a cascade of events leading to plaque rupture [11,12]
We found that SP-8356 has an anti-tumor effect through inhibition of cluster of differentiation 147 (CD147)/MMP-9 pathway [21]
Summary
Atherosclerosis is a major cause of mortality and morbidity worldwide associated with characteristic clinical symptoms, myocardial infarction, and stroke [1,2]. Plaque development and vulnerability to rupture are key processes in atherosclerosis, which lead to critical cardiovascular events through formation of thrombi. MMP-9 facilitates monocyte/macrophage infiltration into plaques through ECM degradation and chemokine modulation, which contributes to increased burden of inflammation, thereby promoting a cascade of events leading to plaque rupture [11,12]. Interactions between CD147 and CypA present a potential therapeutic target to prevent plaque rupture. We further examined whether binding of SP-8356 to CD147 can disrupt its interaction with CypA with consequent suppressive effects on plaque progression. 2. Res2u.2l.tsSP-8356 Reduces CypA-Induced MMP-9 Activation and Monocyte Adhesion. We used the transfection method to obtain secreted extracellular hemagglutinin (HA)-tagged CypA for treatment of mouse macrophage cell line (RAW 264.7) cells. SP-8356 significantly suppressed CD147-CypA interactions in HA-tagged CypA-treated RAW 264.7 cells in a dose-dependent manner (Figure 1D,E)
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