title: Angiotensin II Type 2 Receptor Inhibits Vascular Intimal Proliferation With Activation of PPARγ.
abstract: Angiotensin II type 2 (AT2) receptor stimulation could exert beneficial effects on vascular remodeling. Previously, we reported that AT2 receptor stimulation ameliorated insulin resistance in diabetic mice accompanied by PPARγ activation which also plays a variety of crucial roles in the vasculature. Therefore, this study aimed to investigate the vascular protective effect of the AT2 receptor with activation of PPARγ involving AT2 receptor-interacting protein (ATIP).
  
  
  
  Vascular injury was induced by polyethylene-cuff placement around the femoral artery in C57BL/6J mice. Treatment with compound 21 (C21), an AT2 receptor agonist, decreased neointimal formation, cell proliferation, and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and interleukin-1β, and phosphorylation of nuclear factor-kappa B, and increased PPARγ DNA-binding activity in the injured artery, whereas these inhibitory effects of C21 were attenuated by co-treatment with a PPARγ antagonist, GW9662. Treatment of vascular smooth muscle cells (VSMC) with C21 prepared from smAT2 transgenic mice, which highly express the AT2 receptor in VSMC, increased both PPARγ activity and its DNA-binding activity determined by dual-luciferase assay and electrophoresis mobility shift assay (EMSA), respectively. We observed that ATIP was involved in PPARγ complex formation, and that transfection of siRNA of ATIP1 attenuated the AT2 receptor-mediated increase in PPARγ activity in VSMC. In response to AT2 receptor stimulation, ATIP was translocated from the plasma membrane to the nucleus.
  
  
  
  Our results suggest a new mechanism by which AT2 receptor stimulation activates PPARγ, thereby resulting in amelioration of vascular intimal proliferation, and that ATIP plays an important role in AT2 receptor-mediated PPARγ activation.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan; Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kukida
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan; mmogi@m.ehime-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan; Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Kousei
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakaoka
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Harumi
authors.initials: H
authors.lastname: Kanno
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan; Department of Pediatrics, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Chisaka
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Bai
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Bao-Shuai
authors.initials: BS
authors.lastname: Shan
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan; Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Akinori
authors.initials: A
authors.lastname: Higaki
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan; Department of Pediatrics, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okura
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan;
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima; D047495:PPAR gamma / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013449:Sulfonamides; D013876:Thiophenes; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D066253:Vascular Remodeling
chemical_list: D002352:Carrier Proteins; C488664:Mtus1 protein, mouse; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D047495:PPAR gamma; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; D025521:Tumor Suppressor Proteins
keywords: ATIP; PPARγ; angiotensin II type 2 receptor; blood pressure; hypertension; vascular remodeling.