title: Vascular smooth muscle cell peroxisome proliferator-activated receptor γ protects against endothelin-1-induced oxidative stress and inflammation.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Pparγ gene in VSMC (smPparγ-/-) would exaggerate ET-1-induced vascular injury.
  
  
  
  eET-1, smPparγ-/- and eET-1/smPparγ-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparγ inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparγ-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparγ-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPparγ-/-. Mesenteric artery reactive oxygen species increased in smPparγ and were further enhanced in eET-1/smPparγ-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ and increased further in eET-1/smPparγ-/-. Spleen CD11b+ cells were increased in smPparγ-/- and further enhanced in eET-1/smPparγ-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPparγ-/- but not in eET-1/smPparγ-/-. Spleen T regulatory lymphocytes increased in smPparγ and decreased in eET-1, and decreased further in eET-1/smPparγ-/-.
  
  
  
  VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.
authors.affiliation: aHypertension and Vascular Research Unit, Lady Davis Institute for Medical Research bDepartment of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada cDepartment of Clinical Medicine, State University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil dDepartment of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany eLaboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA *Noureddine Idris-Khodja and Sofiane Ouerd contributed equally to the article.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Idris-Khodja
authors.forename: Sofiane
authors.initials: S
authors.lastname: Ouerd
authors.forename: Michelle
authors.initials: M
authors.lastname: Trindade
authors.forename: Jordan
authors.initials: J
authors.lastname: Gornitsky
authors.forename: Asia
authors.initials: A
authors.lastname: Rehman
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Mario F
authors.initials: MF
authors.lastname: Neves
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester