Hypertension caused by transgenic overexpression of Rac1

Hamdy H. Hassanain, David Gregg, Maria Luisa Marcelo, Jay L. Zweier, Heraldo P. Souza, Balakrishnan Selvakumar, Qi Ma, Moustafa Moustafa-Bayoumi, Phillip F. Binkley, Nicholas A. Flavahan, Mariana Morris, Chunming Dong, Pascal Goldschmidt-Clermont

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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 O 2•- 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 O 2•- 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 α-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.

Original languageEnglish
Pages (from-to)91-100
Number of pages10
JournalAntioxidants and Redox Signaling
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2007

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Hassanain, H. H., Gregg, D., Marcelo, M. L., Zweier, J. L., Souza, H. P., Selvakumar, B., Ma, Q., Moustafa-Bayoumi, M., Binkley, P. F., Flavahan, N. A., Morris, M., Dong, C., & Goldschmidt-Clermont, P. (2007). Hypertension caused by transgenic overexpression of Rac1. Antioxidants and Redox Signaling, 9(1), 91-100. https://doi.org/10.1089/ars.2007.9.91