## 1 Introduction  
Percutaneous coronary intervention (PCI) is a minimally invasive procedure performed to recalize the coronary arteries in patients with atherosclerosis. Despite the high success rate of PCI, twenty percent of patients have a recurrent major adverse cardiac event in three years [1]. Half of these events are attributive to the initial culprit lesion [1]. So far, restenosis and destructive vascular remodeling remain the major drawbacks of PCI [1,2].  
Vascular smooth muscle cell (VSMC) is one of the most important cells in restenosis and vascular remodeling [2]. It switches from a contractile to a synthetic phenotype in response to the injury which increases the stimulatory growth factors or cytokineses such as platelet-derived growth factor (PDGF), interleukin-1, and tumor necrosis factor-\(\alpha\) and causes the migration and the proliferation of VSMCs for tissue repair [3,4]. In addition, more than 55% of neointimal hyperplasia cases involve extracellular matrix proteins [5].  
Connective tissue growth factor (CTGF), also named CCN2, is a member of the CCN gene family, which comprises six extracellular matrix-associated proteins involved in intercellular signaling. CTGF plays important cellular roles in the proliferation and migration of fibroblasts, the production of the extracellular matrix, and cell adhesion. Therefore, it has related biological effects in wound healing and angiogenesis [6, 7, 8]. Previous studies have shown that downregulation of CTGF suppresses neointimal hyperplasia after arterial injury. These suggesting that CTGF may play an important role in-stent restenosis [9].  
Thrombin has been reported to be generated abundantly in smooth muscle cells at the site of PCI and amplified by the formation of the prothrombine complex [10]. Thrombin also mediates several cellular activities involved in the process of restenosis, including smooth muscle cell migration and proliferation [11]. To initiate intracellular signaling, thrombin binds and cleaves the N -terminal domain of the protease-activated receptor (PAR) to expose a new N-terminus.  
PARs are a subfamily of G protein-coupled receptors (GPCRs), and its truncated N-terminus acts as a tethered ligand to initiate its own receptor signal [12,13]. PAR-1 mediates cellular responses to thrombin and related proteases [14]. Activated PAR-1 causes platelets to change shape and aggregate and causes phenotypic changes in neurons, smooth muscle cells, immune cells, epithelial cells, and fibroblasts [15]. In normal arteries, PAR-1 expression is detected in platelets, leukocytes, and endothelial cells [16] but is limited in VSMCs. However, after balloon angioplasty insult, PAR-1 transcription is upregulated in VSMCs [17].  
Magnolol is a hydroxybiphenyl compound extracted from the root and stem bark of Magnolia officinalis. M. officinalis is an important traditional Chinese and Japanese herbal plant that possessesnumerous medicinal properties and is still used in modern clinical practice [18]. Structural analysis has shown that magnolol is an allosteric potentiator of GABAA\({}_{\text{A}}\) receptors [19]. Artificial magnolol linked dimer is an agonist of peroxisome proliferatorator-activated receptor, which resides in the nuclear membrane and plays pivotal roles in maintaining lipid and glucose homeostasis [20]. It has also been reported that treating VSMCs cells with magnolol may induce apoptosis via the intrinsic pathway and has the potential to treat restenosis and atherosclerosis [21]. However, the underlying mechanism of magnolol on which thrombin, CTGF expression, and VSMC proliferation-related restenosis remain unclear.  
We previously found that thrombin can induce CTGF expression in rat VSMCs and acts on PAR-1 to activate the c-Jun N-terminal kinase (JNK) signaling pathway, which in turn initiates activator protein-1 (AP-1) activation and ultimately induces CTGF expression [22]. This study aimed to investigate the mechanisms of magnolol in thrombin-mediated CTGF expression and in balloon injury-induced neointima formation.