Edaravone targets PDGFRβ to attenuate VSMC phenotypic transition
Xueqing Tang1, Dannya Estau2, Xiaoru Huang2
1Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Beijing Key Laboratory of Cardiovascular Receptors Research; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
Aims:
PDGFRβ-driven phenotypic transition of vascular smooth muscle cells (VSMCs) is a pathological hallmark in various cardiovascular diseases, yet effective interventions are lacking. Here, we explored a promising drug targeting PDGFRβ against VSMC phenotypic transition.
Materials And Methods:
Connectivity map (CMAP) analysis was employed to identify the promising drug targeting PDGFRβ against VSMC phenotypic transition. A cell model stimulated with PDGF-BB and a mouse model of femoral artery injury were used to study the effects of edaravone (EDA) on VSMC phenotypic transition and PDGFRβ signaling. Molecular docking, drug affinity responsive target stability (DRATS) and cellular thermal shift assay (CETSA) were used to investigate whether EDA targeted PDGFRβ, which was further validated by a titration experiment.
Key Findings:
Our study revealed that an approved drug EDA might target PDGFRβ against VSMC phenotypic transition. CMAP analysis unraveled EDA as a potential drug related to PDGFRβ. EDA markedly suppressed PDGFRβ-mediated VSMC transition from a contractile to a dedifferentiated phenotype, and reduced neointimal formation in wire-injured arteries. Mechanistically, molecular docking studies showed that EDA interacted with PDGFRβ, which was further confirmed by DRATS and CETSA. Consequently, EDA significantly suppressed PDGFRβ downstream signaling, including AKT and ERK1/2. Furthermore, EDA inhibited VSMC phenotypic transition in a PDGFRβ-dependent manner.
Significance:
Our work identifies EDA as a repurposed drug targeting PDGFRβ to attenuate VSMC phenotypic transition and provide new intervention measures for cardiovascular diseases associated with VSMC phenotypic transition.
