XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

• DOI: 10.1161/atvbaha.115.305420
• Publication Date: 2015-08-28T03:14:10Z
• Authors: Lingfang Zeng; Yi Li; Juanyao Yang; Gang Wang; Andriana Margariti; Qingzhong Xiao; Anna Zampetaki; Xiaoke Yin; Manuel Mayr; Kazutoshi Mori; Wen Wang; Yanhua Hu; Qingbo Xu
• Keywords: Proteomics; 0301 basic medicine; 610; Down-Regulation; Regulatory Factor X Transcription Factors; Signal transduction; Real-Time Polymerase Chain Reaction; Muscle, Smooth, Vascular; Mice; Random Allocation; 03 medical and health sciences; Cell Movement; Neointima; 616; Animals; Vascular remodeling; RNA, Messenger; Cells, Cultured; Cell Proliferation; Platelet-Derived Growth Factor; Receptor Cross-Talk; microRNAs; DNA-Binding Proteins; Femoral Artery; Mice, Inbred C57BL; Disease Models, Animal; Gene Expression Regulation; Inositol; Signal Transduction

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.