taurochenodeoxycholic-acid and Neointima

The role of endoplasmic reticulum (ER) stress in cardiovascular disease is now recognized. Tauroursodeoxycholic acid (TUDCA) is known to have cardiovascular protective effects by decreasing ER stress. This study aimed to assess the ability of TUDCA to decrease ER stress, inhibit dedifferentiation of vascular smooth muscle cells (VSMCs), and reduce in-stent restenosis.. The effect of TUDCA on dedifferentiation of VSMCs and ER stress was investigated in vitro using wound-healing assays, MTT assays, and western blotting. For in vivo studies, 18 rabbits were fed an atherogenic diet to induce atheroma formation. Bare metal stents (BMS), BMS+TUDCA or Firebird stents were implanted in the left common carotid artery. Rabbits were euthanized after 28 days and processed for scanning electron microscope (SEM), histological examination (HE), and immunohistochemistry.. In vitro TUDCA (10-1000 μmol/L) treatment significantly inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration in VSMCs in a concentration-dependent manner and decreased ER stress markers (IRE1, XBP1, KLF4, and GRP78). In vivo, we confirmed no significant difference in neointimal coverage on three stents surfaces; neointimal was significantly lower with BMS+TUDCA (1.6 ± 0.2 mm. TUDCA inhibited dedifferentiation of VSMCs by decreasing ER stress and reduced in-stent restenosis, possibly through downregulation of the IRE1/XBP1 signaling pathway.

Topics: Administration, Oral; Animals; Aorta, Thoracic; Carotid Arteries; Carotid Artery Diseases; Cell Dedifferentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Drug-Eluting Stents; Endoplasmic Reticulum Stress; Endovascular Procedures; Kruppel-Like Factor 4; Male; Membrane Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Protein Serine-Threonine Kinases; Rabbits; Rats, Sprague-Dawley; Recurrence; Signal Transduction; Taurochenodeoxycholic Acid; X-Box Binding Protein 1

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