A vascular smooth muscle cell X-box binding protein 1 and transglutaminase 2 regulatory circuit limits neointimal hyperplasia

• Published in: PloS one 2019-04, Vol.14 (4), p.e0212235-e0212235
• Main Authors: Serrano, Ramon L, Yu, Weifang, Graham, Robert M, Bryan, Ru Liu, Terkeltaub, Robert
• Format: Article
• Language: English
• Subjects: Activating transcription factor 1; Animal models; Animals; Apoptosis; Atherosclerosis; Binding proteins; Biology and Life Sciences; Cardiovascular diseases; Care and treatment; Carotid arteries; Carotid Arteries - cytology; Carotid Arteries - pathology; Carotid Arteries - surgery; Carotid artery; Catalysis; Catalytic activity; Cell Movement; Cell Proliferation; Crosslinking; Cytokines; Disease; Disease Models, Animal; EDTA; Endonuclease; Endoplasmic reticulum; Endoribonucleases - metabolism; Enzymes; Extracellular matrix; Growth factors; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Homeostasis; Humans; Hyperplasia; Hyperplasia - etiology; Hyperplasia - pathology; Injury prevention; Inositol; Ischemia; Ligation - adverse effects; Male; Materials handling equipment; Mediation; Medicine; Medicine and Health Sciences; Mice; Mice, Knockout; Modulators; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - pathology; Muscles; Myocytes, Smooth Muscle - pathology; Neointima - pathology; Nucleases; Oxidative stress; Platelet-derived growth factor; Post-translation; Post-translational modifications; Protein binding; Protein folding; Protein Glutamine gamma Glutamyltransferase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases - metabolism; Proteins; Research and Analysis Methods; Rodents; Signal Transduction; Smooth muscle; Stents; Substrates; Transcription factors; Transglutaminase 2; Transglutaminases; Transglutaminases - genetics; Transglutaminases - metabolism; Ubiquitination; Unfolded Protein Response; Vascular diseases; Vascular smooth muscle; Veins & arteries; Veterans; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212235

Neointimal hyperplasia, stimulated by injury and certain vascular diseases, promotes artery obstruction and tissue ischemia. In vascular smooth muscle cell (VSMCs), multiple modulators of protein handling machinery regulate intimal hyperplasia. These include elements of the VSMC unfolded protein response to endoplasmic reticulum stress (UPRER), and transglutaminase 2 (TG2), which catalyzes post-translational protein modification. Previous results for deficiency of UPRER-specific mediator XBP1, and of TG2, have been significant, but in multiple instances contradictory, for effects on cultured VSMC function, and, using multiple models, for neointimal hyperplasia in vivo. Here, we engineered VSMC-specific deficiency of XBP1, and studied cultured VSMCs, and neointimal hyperplasia in response to carotid artery ligation in vivo. Intimal area almost doubled in Xbp1fl/fl SM22α-CRE+ mice 21 days post-ligation. Cultured murine Xbp1 deficient VSMCs migrated more in response to platelet derived growth factor (PDGF) than control VSMCs, and had an increased level of inositol-requiring enzyme 1α (Ire1α), a PDGF receptor-binding UPRER transmembrane endonuclease whose substrates include XBP1. Cultured XBP1-deficient VSMCs demonstrated decreased levels of TG2 protein, in association with increased TG2 polyubiquitination, but with increased TG transamidation catalytic activity. Moreover, IRE1α, and TG2-specific transamidation cross-links were increased in carotid artery neointima in Xbp1fl/fl SM22α-CRE+ mice. Cultured TG2-deficient VSMCs had decreased XBP1 associated with increased IRE1α, and increased migration in response to PDGF. Neointimal hyperplasia also was significantly increased in Tgm2fl/fl SM22α-CRE+ mice at 21 days after carotid ligation. In conclusion, a VSMC regulatory circuit between XBP1 and TG2 limits neointimal hyperplasia in response to carotid ligation.