on May 13, 2004
Published online before print May 13, 2004, doi: 10.1161/01.ATV.0000132400.25045.2a
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Submitted on April 16, 2004
Accepted on May 4, 2004
Microtubules Regulate Angiotensin II Type 1 Receptor and Rac1 Localization in Caveolae/Lipid Rafts
Lian Zuo ;
From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.
* To whom correspondence should be addressed. E-mail: mfukai{at}emory.edu.
Objective--Microtubules are important in signal transduction temporal-spatial organization. Full expression of angiotensin II (Ang II) signaling in vascular smooth muscle cells (VSMCs) is dependent on the reactive oxygen species (ROS) derived from nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase and the dynamic association of the Ang II type 1 receptor (AT1R) with caveolae/lipid rafts. Translocation of the small GTPase Rac1 to the plasma membrane is an essential step for activation of NAD(P)H oxidase; however, its precise localization in the plasma membrane after agonist stimulation and how it is targeted are unknown. We hypothesized that microtubules are involved in regulating multiphasic Ang II-signaling events in VSMC.
Methods and Results--We show that Ang II promotes Rac1 and AT1R trafficking into caveolae/lipid rafts, which is blocked by disruption of microtubules with nocodazole. As a consequence, nocodazole significantly inhibits Ang II-stimulated H2O2 production, its downstream ROS-dependent epidermal growth factor receptor transactivation, Akt phosphorylation, and vascular hypertrophy without affecting Rac1 activation or ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation.
Conclusions--These results suggest that proper Rac1 and AT1R trafficking into caveolae/lipid rafts requires the integrity of microtubules and provide insight into the essential role of microtubules for the spatial-temporal organization of ROS-dependent and caveolae/lipid rafts-dependent AT1R signaling linked to vascular hypertrophy.
Key words: microtubules • angiotensin II • reactive oxygen species • caveolae • vascular smooth muscle
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