ursodoxicoltaurine and Hyperplasia

Endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) are predominant features of pathological processes. However, little is known about the link between ER stress and endovascular injury. We investigated the involvement of ER stress in neointima hyperplasia after vascular injury. The femoral arteries of 7-8-week-old male mice were subjected to wire-induced vascular injury. After 4 weeks, immunohistological analysis showed that ER stress markers were upregulated in the hyperplastic neointima. Neointima formation was increased by 54.8% in X-box binding protein-1 (XBP1) heterozygous mice, a model of compromised UPR. Knockdown of Xbp1 in human coronary artery smooth muscle cells (CASMC) in vitro promoted cell proliferation and migration. Furthermore, treatment with ER stress reducers, 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), decreased the intima-to-media ratio after wire injury by 50.0% and 72.8%, respectively. Chronic stimulation of CASMC with PDGF-BB activated the UPR, and treatment with 4-PBA and TUDCA significantly suppressed the PDGF-BB-induced ER stress markers in CASMC and the proliferation and migration of CASMC. In conclusion, increased ER stress contributes to neointima formation after vascular injury, while UPR signaling downstream of XBP1 plays a suppressive role. Suppression of ER stress would be a novel strategy against post-angioplasty vascular restenosis.

Topics: Animals; Becaplermin; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Vessels; DNA-Binding Proteins; Endoplasmic Reticulum Stress; Endothelial Cells; Femoral Artery; Gene Expression Regulation; Heterozygote; Humans; Hyperplasia; Male; Mice; Myocytes, Smooth Muscle; Neointima; Phenylbutyrates; Proto-Oncogene Proteins c-sis; Regulatory Factor X Transcription Factors; Signal Transduction; Taurochenodeoxycholic Acid; Transcription Factors; Unfolded Protein Response; Vascular System Injuries; X-Box Binding Protein 1

Hyperplasia of vascular smooth muscle cells (VSMCs) after blood vessel injury is one of the major pathophysiological mechanisms associated with neointima. Tauroursodeoxycholate (TUDCA) is a cytoprotective agent in a variety of cells including hepatocytes as well as an inducer of apoptosis in cancer cells. In this study, we investigated whether TUDCA could prevent neointimal hyperplasia by suppressing the growth and migration of VSMCs.. Transporters of TUDCA uptake in human VSMCs (hVSMCs) were analysed by RT-PCR and western blot. A knock-down experiment using specific si-RNA revealed that TUDCA was incorporated into hVSMCs via organic anion transporter 2 (OATP2). TUDCA reduced the viability of hVSMCs, which were mediated by inhibition of extracellular signal-regulated kinase (ERK) by induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) via protein kinase Cα (PKCα). The anti-proliferative effect of TUDCA was reversed by treatment with 7-hydroxystaurosporine, an inhibitor of PKC, and by the knock-down of MKP-1. In addition, TUDCA suppressed hVSMC migration, which was mediated by reduced matrix metalloproteinase-9 (MMP-9) expression by ERK inhibition, as well as reduced viability of hVSMCs. Rats with carotid artery balloon injury received oral administration of TUDCA; this reduced the increase in ERK and MMP-9 caused by balloon injury. TUDCA significantly decreased the ratio of intima to media by reducing proliferation and inducing apoptosis of the VSMCs.. TUDCA inhibits neointimal hyperplasia by reducing proliferation and inducing apoptosis of smooth muscle cells by suppression of ERK via PKCα-mediated MKP-1 induction.

Topics: Animals; Apoptosis; Biological Transport; Carotid Artery Injuries; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Dual Specificity Phosphatase 1; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Hyperplasia; Liver-Specific Organic Anion Transporter 1; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Protein Kinase C-alpha; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; RNA Interference; Staurosporine; Taurochenodeoxycholic Acid; Time Factors; Transfection; Tunica Intima; Up-Regulation