Abstract
Balloon angioplasty-induced neointimal hyperplasia remains a clinical problem that must be resolved. The bioactivities of the Crossostephium chinense extract (CCE) have demonstrated potential in preventing the progression of restenosis. The present study evaluated whether CCE can suppress balloon angioplasty-induced neointima formation and elucidated its possible pharmacological mechanisms. A rat model of carotid arterial balloon angioplasty was established to evaluate the inhibitory effect of CCEs on neointimal hyperplasia. Two cell lines, A10 vascular smooth muscle cells (VSMCs) and RAW264.7 macrophages, were used to investigate the potential regulatory activities and pharmacological mechanisms of CCEs in cell proliferation and migration and in inflammation. Our in vitro results indicated that CCE3, the ethanolic extract of C. chinense, exerted the strongest growth inhibitory and antimigratory effects on VSMCs. CCE3 blocked the activation of focal adhesion kinase, platelet-derived growth factor receptor-β (PDGFRB), and its downstream molecules (AKT and mTOR) and reduced the expression of matrix metalloproteinase-2. In addition, our findings revealed that CCE3 significantly increased the expression of miRNA-132, an inhibitory regulator of inflammation and restenosis, and suppressed the expression of inflammation-related molecules (inducible nitric oxide synthase, cyclooxygenase-2, interleukin- (IL-) 1β, and IL-6). Our in vivo study results indicated that balloon injury-induced neointimal hyperplasia was inhibited by CCE3. CCE3 could reduce neointima formation in balloon-injured arteries, and this effect may be partially attributed to the CCE3-induced suppression of PDGFRB-mediated downstream pathways and inflammation-related molecules.
Highlights
Percutaneous coronary intervention is a common surgical procedure used to reopen an acute arterial obstruction by inserting a balloon catheter in occlusive sites, followed by intraluminal inflation
Our analysis results verified that water and ethanolic extracts, namely, CCE1 and CCE3, respectively, had more polar compounds eluted rapidly at the early stage of separation, and ingredients with lower polarity were observed in the hexane extract CCE2
To determine the Crossostephium chinense extract (CCE) with the strongest potential to suppress vascular smooth muscle cells (VSMCs) viability, we examined the cytotoxicity of CCE1, CCE2, and CCE3 by using the methylthialazole tetrazolium (MTT) assay (Figure 2(a)). e results indicated that CCE3 exhibited the strongest activity for inhibiting 10% fetal bovine serum (FBS)-stimulated cell proliferation, and CCE1 and CCE2 exerted no significant effects on growth inhibition at the tested concentrations
Summary
Percutaneous coronary intervention is a common surgical procedure used to reopen an acute arterial obstruction by inserting a balloon catheter in occlusive sites, followed by intraluminal inflation. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) have been verified to play key pathological roles in the progression of neointimal hyperplasia; VSMCs have become a potential therapeutic target for restenosis induced by vascular drug-eluting stents [3, 4] Some regulatory factors, such as platelet-derived growth factor (PDGF) and inflammation, play crucial pathological roles in VSMCs during neointima formation. PDGF can upregulate the expression of monocyte chemoattractant protein-1 (MCP-1) to recruit macrophages and monocytes to injured tissues for participation in local inflammation [11, 12] Inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-6, released from recruited immunocytes can exacerbate VSMC proliferation and migration and neointimal hyperplasia [13, 14], and therapeutic interventions that involve the suppression of inflammation can alleviate neointima formation [15, 16]. Inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-6, released from recruited immunocytes can exacerbate VSMC proliferation and migration and neointimal hyperplasia [13, 14], and therapeutic interventions that involve the suppression of inflammation can alleviate neointima formation [15, 16]. e aforementioned studies have provided evidence for the pathological roles of PDGF and inflammation in the progression of restenosis and have indicated the complex relationship between restenosis and these pathological factors
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