Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth

American Journal of Physiology. Lung Cellular and Molecular Physiology
Sandip PatilStephen M Black

Abstract

Vascular NADPH oxidases have been shown to be a major source of reactive oxygen species (ROS). Recent studies have also implicated ROS in the proliferation of vascular smooth muscle cells. However, the components required for activation of the NADPH oxidase complex have not been clearly elucidated. Here we demonstrate that ROS generation in ovine pulmonary arterial smooth muscle cells (PASMCs) requires the activation of Rac1, implicating this protein as an important subunit of the NADPH oxidase complex. Our results, using a geranylgeranyl transferase inhibitor (GGTI-287), demonstrated a dose-dependent inhibition of Rac1 activity and ROS production. This was associated with an inhibition of PASMC proliferation with an arrest at G(2)/M. The inhibition of Rac1 by GGTI-287 led us to more specifically target Rac1 to investigate its role in the generation of ROS and cellular proliferation. To accomplish this, we utilized a dominant negative Rac1 (N17Rac1) and a constitutively active Rac1 (V12Rac1). These two forms of Rac1 were transiently expressed in PASMCs using adenovirus-mediated gene transfer. N17Rac1 expression resulted in decreased cellular Rac1 activity, whereas V12Rac1 infection showed increased activity. Compared with contr...Continue Reading

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Citations

Jan 24, 2009·Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Für Klinische Und Experimentelle Ophthalmologie·Peng ZhangJian Zhou
Dec 20, 2013·Antioxidants & Redox Signaling·Stephen Wedgwood, Robin H Steinhorn
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Nov 26, 2015·Tissue & Cell·Yoshiaki KashiwabaraHiroki Watanabe
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Jun 12, 2013·Biochimica Et Biophysica Acta·Marisa A Gallicchio, Leon A Bach
Jan 19, 2013·Therapeutic Advances in Respiratory Disease·Véronique Freund-MichelBernard Muller
Jun 10, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·Matthias OelzeThomas Münzel
Dec 16, 2005·American Journal of Physiology. Cell Physiology·Alice-Corina CeacareanuAviv Hassid
May 11, 2006·American Journal of Physiology. Lung Cellular and Molecular Physiology·Albert C GrobeStephen M Black
Jan 24, 2007·Physiological Reviews·Karen Bedard, Karl-Heinz Krause
Oct 21, 2010·Physiological Reviews·Yuansheng Gao, J Usha Raj

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