title: Fasudil inhibits ER stress-induced VCAM-1 expression by modulating unfolded protein response in endothelial cells.
abstract: The process of atherosclerosis is affected by interactions among numerous biological pathways. Accumulating evidence shows that endoplasmic reticulum (ER) stress plays a crucial role in the development of atherosclerosis. Rho-kinase is an effector of small GTP-binding protein Rho, and has been implicated as an atherogenic factor. Previous studies demonstrated that fasudil, a specific Rho-kinase inhibitor, exerts a cardioprotective effect by downregulating ER stress signaling. However, the molecular link between ER stress and Rho-kinase in endothelial cells has not been elucidated. In this study, we investigated the mechanisms by which fasudil regulates endothelial inflammation during ER stress. Tunicamycin, an established ER stress inducer, increased vascular cellular adhesion molecule (VCAM)-1 expression in endothelial cells. Intriguingly, fasudil inhibited VCAM-1 induction. From a mechanistic stand point, fasudil inhibited expression of activating transcription factor (ATF)4 and subsequent C/EBP homologous protein (CHOP) induction by tunicamycin. Furthermore, fasudil attenuated tunicamycin-induced phophorylation of p38MAPK that is crucial for the atherogenic response during ER stress. These findings indicate that Rho-kinase regulates ER stress-mediated VCAM-1 induction by ATF4- and p38MAPK-dependent signaling pathways. Rho-kinase inhibition by fasudil would be an important therapeutic approach against atherosclerosis, in particular, under conditions of ER stress.
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan. daijika@jikei.ac.jp
authors.forename: Daiji
authors.initials: D
authors.lastname: Kawanami
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Matoba
authors.forename: Rina
authors.initials: R
authors.lastname: Okada
authors.forename: Masami
authors.initials: M
authors.lastname: Tsukamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.forename: Sho
authors.initials: S
authors.lastname: Ishizawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yokota
authors.forename: Kazunori
authors.initials: K
authors.lastname: Utsunomiya
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017510:Protein Folding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013312:Stress, Physiological; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil