Abstract
Angiotensin II (Ang II)-mediated modification of the redox milieu of vascular smooth muscle cells (VSMCs) has been implicated in several pathophysiological processes, including cell proliferation, migration and differentiation. In this study, we demonstrate that the peroxisome proliferator-activated receptor (PPAR) δ counteracts Ang II-induced production of reactive oxygen species (ROS) in VSMCs. Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly reduced Ang II-induced ROS generation in VSMCs. This effect was, however, reversed in the presence of small interfering (si)RNA against PPARδ. The marked increase in ROS levels induced by Ang II was also eliminated by the inhibition of phosphatidylinositol 3-kinase (PI3K) but not of protein kinase C, suggesting the involvement of the PI3K/Akt signalling pathway in this process. Accordingly, ablation of Akt with siRNA further enhanced the inhibitory effects of GW501516 in Ang II-induced superoxide production. Ligand-activated PPARδ also blocked Ang II-induced translocation of Rac1 to the cell membrane, inhibiting the activation of NADPH oxidases and consequently ROS generation. These results indicate that ligand-activated PPARδ plays an important role in the cellular response to oxidative stress by decreasing ROS generated by Ang II in vascular cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / antagonists & inhibitors
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Angiotensin II / pharmacology*
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cells, Cultured
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Gene Expression Regulation / drug effects
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Humans
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism*
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NADPH Oxidases / antagonists & inhibitors
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NADPH Oxidases / metabolism
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Oxidative Stress / drug effects
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PPAR gamma / agonists*
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Reactive Oxygen Species / antagonists & inhibitors*
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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Thiazoles / pharmacology
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rac1 GTP-Binding Protein / antagonists & inhibitors*
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rac1 GTP-Binding Protein / metabolism
Substances
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GW 501516
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PPAR gamma
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Phosphoinositide-3 Kinase Inhibitors
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RAC1 protein, human
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Reactive Oxygen Species
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Thiazoles
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Angiotensin II
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NADPH Oxidases
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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rac1 GTP-Binding Protein