Hypertension caused by transgenic overexpression of Rac1.
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.
Hassanain
Hamdy H
HH
Department of Anesthesiology, Dorothy M. Davis Heart and Lung Institute, The Ohio State University, Columbus, Ohio 43210, USA. hamdy.hasssanain@osumc.edu
Gregg
David
D
Marcelo
Maria Luisa
ML
Zweier
Jay L
JL
Souza
Heraldo P
HP
Selvakumar
Balakrishnan
B
Ma
Qi
Q
Moustafa-Bayoumi
Moustafa
M
Binkley
Phillip F
PF
Flavahan
Nicholas A
NA
Morris
Mariana
M
Dong
Chunming
C
Goldschmidt-Clermont
Pascal J
PJ
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*
D000199:Actins; D000975:Antioxidants; D011506:Proteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D012083:Renin; D020830:rac1 GTP-Binding Protein