Abstract
Restenosis and destructive vascular remodeling are the main reasons for treatment failure in patients undergoing percutaneous coronary intervention (PCI). In this study, we explored the efficacy of magnolol (a traditional Chinese medicine) in the treatment of restenosis. The results of this study showed that the activities of thrombin and PAR-1 (protease-activated receptor 1) were significantly decreased by the treatment of magnolol. Based on protein docking analysis, magnolol exhibits its potential to bind to the PAR-1 active site. In addition, thrombin-induced connective tissue growth factor (CTGF) expression and the upstream of CTGF such as JNK-1 (but not JNK-2), c-Jun, and AP-1 were distinctly inhibited by magnolol (50 μM) in vascular smooth muscle cells (VSMC). For the functional assay, magnolol (50 μM) significantly inhibited the migration of VSMC, and rats treated with magnolol (13 mg/kg/day) after balloon angioplasty has observed a significant reduction in the formation of common arterial neointima. In conclusion, we identified a novel mechanism by which magnolol acts as the thrombin activity inhibitor and may be the PAR-1 antagonist. In accordance with these functions, magnolol could decrease thrombin-induced CTGF expression in VSMCs via PAR-1/JNK-1/AP-1 signaling.
Highlights
Percutaneous coronary intervention (PCI) is a minimally invasive procedure performed to recanalize the coronary arteries in patients with atherosclerosis
We previously found that thrombin can induce connective tissue growth factor (CTGF) expression in rat Vascular smooth muscle cell (VSMC) and acts on protease-activated receptor (PAR)-1 to activate the c-Jun N-terminal kinase (JNK) signaling pathway, which in turn initiates activator protein-1 (AP-1) activation and induces CTGF expression [22]
To understand whether magnolol plays a role in the thrombin-induced CTGF expression, we analyzed the activity of thrombin and the cleavage level of protease-activated receptor-1 (PAR-1) after magnolol and thrombin treatment
Summary
Percutaneous coronary intervention (PCI) is a minimally invasive procedure performed to recanalize 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]. 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-α and causes the migration and the proliferation of VSMCs for tissue repair [3,4]. More than 55% of neointimal hyperplasia cases involve extracellular matrix proteins [5]
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