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Farrerol maintains the contractile phenotype of VSMCs via inactivating the extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase signaling

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Abstract

Farrerol, a dihydroflavone isolated from Rhododendron dauricum L., can inhibit vascular smooth muscle cell (VSMC) proliferation and exert a protective effect on H2O2-induced vascular endothelial cells injury. In this study, we investigated the effects of farrerol on VSMC phenotypic modulation and balloon injury-induced vascular neointimal formation and explored the underlying mechanisms. Serum-starved rat thoracic aorta SMCs (RASMCs) were first pretreated with farrerol (3, 10, and 30 μM, respectively), U0126 (a MEK kinase inhibitor), and SB203580 (a p38 kinase inhibitor), and followed by treatment with serum (10% FBS). The expression of several VSMC-specific markers, including α-SMA, SM22α, and OPN, were analyzed by western blot. Phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (MAPK) was also investigated. Farrerol inhibited the serum-induced transition of RASMCs from the contractile to the synthetic phenotype, and this was associated with a decrease in α-SMA and SM22α expression, and an increase in OPN expression. Farrerol also inhibited serum-induced phosphorylation of ERK1/2 and p38MAPK in RASMCs. Moreover, U0126 and SB203580 both inhibited the serum-induced phenotypic transition of RASMCs. These findings indicate that farrerol can maintain the contractile phenotype of VSMCs partly via inactivating the ERK1/2 and p38 MAPK signaling pathways. Using a rat model of carotid artery balloon injury, inhibition of VSMC phenotypic transition and suppression of neointimal formation were confirmed in vivo following the perivascular application of farrerol. Our results suggested that farrerol could be a promising lead compound for the treatment of vascular proliferative diseases.

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Funding

This work was financially supported by the National Natural Science Foundation of China (No. 81172938), the Natural Science Foundation for Young Scientists of Shanxi Province (201601D021158); and the Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation Shanxi University of Chinese Medicine (SXIDL-2018–03).

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Authors and Affiliations

  1. School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Tai Yuan, 030001, Shan xi, China

    Enli Liu, Shasha Shi, Jie Li, Rui Ge, Taigang Liang & Qingshan Li

  2. Shanxi Key Laboratory of Chronic Inflammatory Targeted Drugs, School of Materia Medica, Shanxi University of Traditional Chinese Medicine, 121 University Street, Jinzhong, 030602, Shanxi, China

    Qingshan Li

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QL, EL, and TL conceived and designed the experiments. EL, SS, and JL performed the experiments. EL wrote the manuscript. EL and RG performed the data analysis. All authors reviewed and approved the final manuscript.

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Correspondence to Qingshan Li.

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Liu, E., Shi, S., Li, J. et al. Farrerol maintains the contractile phenotype of VSMCs via inactivating the extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase signaling. Mol Cell Biochem 475, 249–260 (2020). https://doi.org/10.1007/s11010-020-03878-5

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