Kahweol, a Diterpenoid Molecule, Inhibits CTGF-Dependent Synthetic Phenotype Switching and Migration in Vascular Smooth Muscle Cells

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.

Unraveling Connective Tissue Growth Factor as a Therapeutic Target and Assessing Kahweol as a Potential Drug Candidate in Triple-Negative Breast Cancer Treatment

“…According to a recent meta-analysis, roughly 33% of individuals with TNBC will ultimately experience brain metastasis [36]. In a previous study, recombinant CTGF proteins increased VSMC migration and the expression of FAK and the yes-associated protein (YAP), which is related to the formation of focal adhesion and cell migration [23]. It has been demonstrated that the upregulation of CTGF leads to an increase in the expression of matrix metalloproteinases, such as matrix metalloproteinase (MMP)-2 and MMP-3, consequently stimulating cell migration in osteosarcoma [31].…”

“…In our previous study, kahweol suppressed CTGF expression in VSMCs [23]. To determine whether kahweol inhibits CTGF expression in TNBC, the mRNA level of CTGF was investigated.…”

“…It has been reported that kahweol not only induces antiproliferative effect and apoptosis in several cancers including HER2-positive breast, colorectal, and non-small cell lung cancers [18][19][20] but also significantly inhibits cell migration in prostate and renal cancers [21,22]. In a previous study, we demonstrated that kahweol suppresses Angiotensin II-induced migration through the inhibition of CTGF expression in vascular smooth muscle cells (VSMCs) [23]. Few studies on the association between kahweol and CTGF have been additionally reported in the hepatic fibrosis [24,25].…”

lncRNA MIR503HG Targets miR-191-5p/PLCD1 Axis and Negatively Modulates Apoptosis, Extracellular Matrix Disruption, and Inflammation in Abdominal Aortic Aneurysm

“…More apoptotic and synthetic VSMCs as well as induced inflammation are Mediators of Inflammation observed in AAA progression. The apoptotic VSMCs result in the numerous loss of contractile cells and thus promoting the expansion of the abdominal aortic wall [27]. Furthermore, it has been revealed that inflammation could secrete MMP, which can further degrade the components of the ECM and cause ECM disruption.…”

Endothelial-derived extracellular microRNA-92a promotes arterial stiffness by regulating phenotype changes of vascular smooth muscle cells

“…Thus, besides miR-92a, the proteins targeted by miR-92a may also participate in the EC-VSMC crosstalk. Several studies have reported that Ang II induces the proliferative phenotypic change of VSMCs 25 , 26 . We also detected the level of miR-92a in VSMCs treated with Ang II, and found that Ang II increased the expression of miR-92a in VSMCs (Supplementary Fig.…”