Lingfang Zeng1, Yi Li2, Juanyao Yang2, Gang Wang2, Andriana Margariti2, Qingzhong Xiao2, Anna Zampetaki2, Xiaoke Yin2, Manuel Mayr2, Kazutoshi Mori2, Wen Wang2, Yanhua Hu2, Qingbo Xu1. 1. From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.). lingfang.zeng@kcl.ac.uk qingbo.xu@kcl.ac.uk. 2. From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
Abstract
OBJECTIVE: Smooth muscle cell (SMC) migration and proliferation play an essential role in neointimal formation after vascular injury. In this study, we intended to investigate whether the X-box-binding protein 1 (XBP1) was involved in these processes. APPROACH AND RESULTS: In vivo studies on femoral artery injury models revealed that vascular injury triggered an immediate upregulation of XBP1 expression and splicing in vascular SMCs and that XBP1 deficiency in SMCs significantly abrogated neointimal formation in the injured vessels. In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor β and the inositol-requiring enzyme 1α. The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). XBP1s directed the transcription of mir-1274B that targeted CNN1 mRNA degradation. Proteomic analysis of culture media revealed that XBP1s decreased transforming growth factor (TGF)-β family proteins secretion via transcriptional suppression. TGF-β3 but not TGF-β1 or TGF-β2 attenuated XBP1s-induced CNN1 decrease and SMC proliferation. CONCLUSIONS: This study demonstrates for the first time that XBP1 is crucial for SMC proliferation via modulating the platelet-derived growth factor/TGF-β pathways, leading to neointimal formation.
OBJECTIVE: Smooth muscle cell (SMC) migration and proliferation play an essential role in neointimal formation after vascular injury. In this study, we intended to investigate whether the X-box-binding protein 1 (XBP1) was involved in these processes. APPROACH AND RESULTS: In vivo studies on femoral artery injury models revealed that vascular injury triggered an immediate upregulation of XBP1 expression and splicing in vascular SMCs and that XBP1 deficiency in SMCs significantly abrogated neointimal formation in the injured vessels. In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor β and the inositol-requiring enzyme 1α. The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). XBP1s directed the transcription of mir-1274B that targeted CNN1 mRNA degradation. Proteomic analysis of culture media revealed that XBP1s decreased transforming growth factor (TGF)-β family proteins secretion via transcriptional suppression. TGF-β3 but not TGF-β1 or TGF-β2 attenuated XBP1s-induced CNN1 decrease and SMC proliferation. CONCLUSIONS: This study demonstrates for the first time that XBP1 is crucial for SMC proliferation via modulating the platelet-derived growth factor/TGF-β pathways, leading to neointimal formation.
Authors: Mingyi Wang; Li Zhang; Wanqu Zhu; Jing Zhang; Soo Hyuk Kim; Yushi Wang; Leng Ni; Richard Telljohann; Robert E Monticone; Kimberly McGraw; Lijuan Liu; Rafael de Cabo; Edward G Lakatta Journal: J Am Heart Assoc Date: 2018-09-18 Impact factor: 5.501