title: Hypertension caused by transgenic overexpression of Rac1.
abstract: Reactive oxygen species, including superoxide, are important mediators of the pathophysiology of hypertension. In the vasculature, superoxide antagonizes nitric oxide (NO*), resulting in increased vascular tone. The GTP binding protein Rac regulates a wide variety of cellular functions, including the activation of NADPH oxidase, the major source of O2*-in the blood vessel wall. An hypothesis is that Rac1 may act as an important regulator of vascular O2*- production, contributing to the balance between O2*- and NO* and maintaining consequent homeostasis of blood pressure. To alter the activity of vascular NADPH oxidase, the authors developed a transgenic animal model that overexpresses the human cDNA of the constitutively active mutant of Rac1 (RacCA) in smooth muscle cells using the smooth muscle +/--actin promoter. The RacCA transgenic had excessive amounts of O2*- in the vessel wall that, which led to heightened production of peroxynitrite, as detected by increased protein nitration and reduced NO* levels. RacCA mice developed moderate hypertension, which was corrected by N-acetyl-L-cysteine (NAC). RacCA transgenic mice also developed left ventricular hypertrophy as a secondary effect of pressure overload. The data suggest that Rac1 is a critical regulator of the redox state of blood vessels and homeostasis of blood pressure.
authors.affiliation: Department of Anesthesiology, Dorothy M. Davis Heart and Lung Institute, The Ohio State University, Columbus, Ohio 43210, USA. hamdy.hasssanain@osumc.edu
authors.forename: Hamdy H
authors.initials: HH
authors.lastname: Hassanain
authors.forename: David
authors.initials: D
authors.lastname: Gregg
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Marcelo
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Heraldo P
authors.initials: HP
authors.lastname: Souza
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Selvakumar
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.forename: Moustafa
authors.initials: M
authors.lastname: Moustafa-Bayoumi
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Binkley
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Flavahan
authors.forename: Mariana
authors.initials: M
authors.lastname: Morris
authors.forename: Chunming
authors.initials: C
authors.lastname: Dong
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics; D005260:Female; D006973:Hypertension / Q000209:etiology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D014018:Tissue Distribution; D019076:Transgenes; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D000975:Antioxidants; D011506:Proteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D012083:Renin; D020830:rac1 GTP-Binding Protein