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on July 1, 2005

Arteriosclerosis, Thrombosis, and Vascular Biology. 2005
Published online before print June 23, 2005, doi: 10.1161/01.ATV.0000175295.09607.18
A more recent version of this article appeared on September 1, 2005
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Submitted on April 18, 2005
Accepted on June 9, 2005

Caveolin-1 Is Essential for Activation of Rac1 and NAD(P)H Oxidase After Angiotensin II Type 1 Receptor Stimulation in Vascular Smooth Muscle Cells. Role in Redox Signaling and Vascular Hypertrophy

Lian Zuo ; Masuko Ushio-Fukai *; Satoshi Ikeda ; Lula Hilenski ; Nikolay Patrushev ; and R. Wayne Alexander

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--Angiotensin II (Ang II) is a potent mediator of vascular hypertrophy in vascular smooth muscle cells (VSMCs). These effects are mediated through the Ang II type 1 receptor (AT1R) and require its trafficking through caveolin-1 (Cav1)-enriched lipid rafts and reactive oxygen species (ROS) derived from Rac1-dependent NAD(P)H oxidase. The specific role(s) of Cav1 in AT1R signaling is incompletely understood.

Methods and Results--Knockdown of Cav1 protein by small interfering RNA (siRNA) inhibits Ang II-stimulated Rac1 activation and membrane translocation, H2O2 production, ROS-dependent epidermal growth factor receptor (EGF-R) transactivation, and subsequent phosphorylation of Akt without affecting ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation. Ang II stimulates tyrosine phosphorylation of Sos-1, a Rac-guanine nucleotide exchange factor, which is inhibited by Cav1 siRNA, demonstrating involvement of Cav1 in Rac1 activation. Detergent-free fractionation showed that EGF-Rs are found basally in Cav1-enriched lipid raft membranes and associate with Cav1. Ang II stimulates AT1R movement into these microdomains contemporaneously with the egress of EGF-R. Both aspects of this bidirectional receptor trafficking are inhibited by Cav1 siRNA. Moreover, Cav1 siRNA inhibits Ang II-induced vascular hypertrophy.

Conclusions--Cav1 plays an essential role in AT1R targeting into Cav1-enriched lipid rafts and Rac1 activation, which are required for proper organization of ROS-dependent Ang II signaling linked to VSMC hypertrophy.
Key words: angiotensin II • reactive oxygen species • caveolin • caveolae • vascular hypertrophy • vascular smooth muscle




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