title: Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways.
abstract: The aim of this study is to elucidate to what degree adiponectin is involved in TZD-mediated amelioration of neointimal formation. We investigated the effect of 3- or 8-weeks' pioglitazone on cuff-induced neointimal formation in adiponectin-deficient (APN-KO) and wild-type (WT) mice. Pioglitazone for 3 weeks reduced neointimal formation in the WT mice with upregulation of the plasma adiponectin levels, but failed to reduce neointimal formation in the APN-KO mice, suggesting that pioglitazone suppressed neointimal formation by adiponectin-dependent mechanisms. Pioglitazone for 3 weeks suppressed vascular smooth muscle cell (VSMC) proliferation and increased AdipoR2 expression in the WT mice. In vitro, globular adiponectin activated AMPK through both AdipoR1 and AdipoR2, resulting in the inhibition of VSMC proliferation. Interestingly, 8-weeks' pioglitazone was reduced neointimal formation in APN-KO mice to degree similar to that seen in the WT mice, suggesting that pioglitazone can also suppress neointimal formation via a mechanism independent of adiponectin. Pioglitazone for 8 weeks completely abrogated the increased VSMC proliferation, along with a reduction of cyclin B1 and cyclin D1 expressions and cardiovascular risk profile in the APN-KO mice. In vitro, pioglitazone suppressed these expressions, leading to inhibition of VSMC proliferation. Pioglitazone suppresses neointimal formation via both adiponectin-dependent and adiponectin-independent mechanisms.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.|Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.|Department of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan.|Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo 153-8515, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.|Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.|Department of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan.|Department of Clinical Nutrition Therapy, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.|Department of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kumagai
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Iwamura
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo 142-8501, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo 153-8515, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Moroi
authors.affiliation: Department of Diabetes and Endocrinology, Yokohama City University, School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D052242:Adiponectin / Q000097:blood* / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D054419:Receptors, Adiponectin / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D054419:Receptors, Adiponectin; D045162:Thiazolidinediones; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D000077205:Pioglitazone