Abstract
Vascular smooth muscle cell (VSMC) phenotype switching from contractile to synthetic is essential for proliferation and migration in vascular pathophysiology. Connective tissue growth factor (CTGF) is a matricellular protein involved in cell adhesion, migration, and proliferation. Kahweol, a diterpene molecule in arabica coffee beans, has been reported to have anti-inflammatory, antiproliferative, and apoptotic effects in many cells. However, in VSMCs, the effects of kahweol on CTGF activities have not been investigated. Thus, in this study, the effects and associated mechanisms of kahweol in CTGF-dependent phenotype switching and migration in VSMCs were examined. Experiments were performed on primary rat aortic smooth muscle cells and a rat VSMC line, A7r5. Western blot analysis was used to determine the protein levels. The mRNA levels of synthetic markers were measured by qRT-PCR. Migration of VSMCs was evaluated by wound healing and transwell assays. Kahweol reduced the angiotensin II (Ang II)-induced CTGF expression. Further, kahweol inhibited expressions of synthetic phenotype markers of VSMC. The kahweol-reduced synthetic marker protein levels were reversed by the administration of rCTGF. However, expressions of contractile phenotype markers of VSMC were not affected. Kahweol suppressed Ang II-stimulated VSMC migration. Moreover, kahweol downregulated Ang II-induced p-FAK, p-Erk, and Yes-associated protein (YAP) protein expressions. Taken together, in Ang II-stimulated VSMCs, kahweol inhibited CTGF-dependent synthetic phenotype switching and migration, with focal adhesion kinase (FAK), Erk, and YAP involved in the underlying mechanisms of the kahweol effects. These results suggest that kahweol has a potential as a therapeutic agent to inhibit CTGF, which is a molecular target in sclerogenic vascular disease.
Highlights
The prevalence of metabolic syndrome is a global trend, and the incidence of cardiovascular diseases, including atherosclerosis, a complication of metabolic syndrome, is steadily increasing [1,2]
In MTT assay, cell viability was not significantly affected at 5 and 10 μM of kahweol. These results indicate that kahweol suppresses angiotensin II (Ang II)-induced Connective tissue growth factor (CTGF) expression in Vascular smooth muscle cell (VSMC)
It was demonstrated that advanced glycation end product (AGE) and high glucose levels could induce the expression of CTGF via extracellular signal regulated kinase (Erk) and c-Jun N-terminal kinase (JNK) phosphorylation, respectively, resulting in the induction of proliferation, migration, and extracellular matrix (ECM) production in VSMCs [26,31]
Summary
The prevalence of metabolic syndrome is a global trend, and the incidence of cardiovascular diseases, including atherosclerosis, a complication of metabolic syndrome, is steadily increasing [1,2]. Treatments for atherosclerosis are based on controlling risk factors such as obesity, hypertension, hyperglycemia, and hyperlipidemia [3]. These treatments are limited in preventing the molecular causes involved in the development of atherosclerosis. In the development of atherosclerosis, endothelial, and immune cells release various stimulating factors, including angiotensin II (Ang II) that induces synthetic VSMCs. Synthetic VSMCs are able to migrate from the media layer to the intima, and migrated VSMCs produce extracellular matrix (ECM) proteins in the intima, which results in increased artery wall thickness and stiffness [4,5,6,7,8]. Because regulation of synthetic VSMCs has pivotal roles in the pathophysiology of atherosclerosis, it may be a key target for cardiovascular interventions
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