All-Trans Retinoic Acid Prevented Vein Grafts Stenosis by Inhibiting Rb-E2F Mediated Cell Cycle Progression and KLF5-RAR
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ORIGINAL ARTICLE
All-Trans Retinoic Acid Prevented Vein Grafts Stenosis by Inhibiting Rb-E2F Mediated Cell Cycle Progression and KLF5-RARα Interaction in Human Vein Smooth Muscle Cells Yongchao Yu 1 & Yang Wang 1,2 & Xiang Fei 1 & Zhigang Song 1 & Feng Xie 1 & Fan Yang 1 & Xiaohong Liu 1 & Zhiyun Xu 1 & Guokun Wang 1 Accepted: 24 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Vein graft failure (VGF) is an important limitation for coronary artery bypass graft (CABG) surgery. Inhibition of the excessive proliferation and migration of venous smooth muscle cells (SMCs) is an effective strategy to alleviate VGF during the CABG perioperative period. In the present study, we aimed to explore the role and potential mechanism of all-trans retinoic acid (ATRA) on preventing vein grafts stenosis. Methods The autogenous vein grafts model was established in the right jugular artery of rabbits. Immunohistochemistry staining and western blot assays were used to detected the protein expression, while real-time PCR assay was applied for mRNAs expression detection. The interaction between proteins was identified by co-immunoprecipitation assay. The Cell Counting Kit-8 and wound-healing assays were used to investigate the role of ATRA on human umbilical vein smooth muscle cells (HUVSMCs) function. Cell cycle progression was identified by flow cytometry assay. Results Vein graft stenosis and SMCs hyperproliferation were confirmed in vein grafts by histological and Ki-67 immunohistochemistry assays. Treatment of ATRA (10 mg/kg/day) significantly mitigated the stenosis extent of vein grafts, demonstrated by the decreased thickness of intima-media, and decreased Ki-67 expression. ATRA could repress the PDGF-bb-induced excessive proliferation and migration of HUVSMCs, which was mediated by Rb-E2F dependent cell cycle inhibition. Meanwhile, ATRA could reduce the interaction between KLF5 and RARα, thereby inhibiting the function of cis-elements of KLF5. KLF5-induced inducible nitric oxide synthase (iNOS) expression activation could be significantly inhibited by ATRA. Conclusions These results suggested that ATRA treatment may represent an effective prevention and therapy avenue for VGF.
Yongchao Yu, Yang Wang and Xiang Fei contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10557-020-07089-4) contains supplementary material, which is available to authorized users. * Xiaohong Liu [email protected] * Zhiyun Xu [email protected] * Guokun Wang [email protected] 1
Institute of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China
2
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210018, China
Keywords All-trans retinoic acid . Vein grafts stenosis . Rb-E2F pathway . Krüppel-like factor 5 . Vein smooth muscle cells
Introduction Coronary artery bypass g
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