XBP 1-deficiency abrogates neointimal lesion of injured vessels via cross talk with the PDGF signaling

TY - JOUR

T1 - XBP 1-deficiency abrogates neointimal lesion of injured vessels via cross talk with the PDGF signaling

AU - Zeng, Lingfang

AU - Li, Yi

AU - Yang, Juanyao

AU - Wang, Gang

AU - Margariti, Andriana

AU - Xiao, Qingzhong

AU - Zampetaki, Anna

AU - Yin, Xiaoke

AU - Mayr, Manuel

AU - Mori, Kazutoshi

AU - Wang, Wen

AU - Hu, Yanhua

AU - Xu, Qingbo

PY - 2015/10/25

Y1 - 2015/10/25

N2 - 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 inositolrequiring 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.

AB - 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 inositolrequiring 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.

KW - Inositol

KW - microRNAs

KW - Proteomics

KW - Signal transduction

KW - Vascular remodeling

UR - http://www.scopus.com/inward/record.url?scp=84942288066&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.115.305420

DO - 10.1161/ATVBAHA.115.305420

M3 - Article

AN - SCOPUS:84942288066

SN - 1079-5642

VL - 35

SP - 2134

EP - 2144

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 10

ER -